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The ubiquitin-proteasome system (UPS), which involves E3 ligases and deubiquitinates (DUBs), is critical for protein homeostasis. The epigenetic reader ZMYND8 (zinc finger MYND-type containing 8) has emerged as an oncoprotein, and its protein levels are elevated in various types of cancer, including breast cancer. However, the mechanism by which ZMYND8 protein levels are increased in cancer remains elusive. Although ZMYND8 has been reported to be regulated by the E3 ligase FBXW7, it is still unknown whether ZMYND8 could be modulated by DUBs. Here, we identified USP7 (ubiquitin carboxyl-terminal hydrolase 7) as a bona fide DUB for ZMYND8. Mechanically, USP7 directly binds to the PBP (PHD-BRD-PWWP) domain of ZMYND8 via its TRAF (tumor necrosis factor receptor-associated factor) domain and UBL (ubiquitin-like) domain and removes F-box and WD repeat domain containing 7 (FBXW7)-catalyzed poly-ubiquitin chains on lysine residue 1034 (K1034) within ZMYND8, thereby stabilizing ZMYND8 and stimulating the transcription of ZMYND8 target genes ZEB1 (zinc finger E-box binding homeobox 1) and VEGFA (Vascular Endothelial Growth Factor A). Consequently, USP7 enhances the capacity of breast cancer cells for migration and invasion through antagonizing FBXW7-mediated ZMYND8 degradation. Importantly, the protein levels of USP7 positively correlates with those of ZMYND8 in breast cancer tissues. These findings delineate an important layer of migration and invasion regulation by the USP7-ZMYND8 axis in breast cancer cells., Competing Interests: Conflict of interest The authors declare that they have no conflict of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The Integrator complex attenuates gene expression via the premature termination of RNA polymerase II (RNAP2) at promoter-proximal pausing sites. It is required for stimulus response, cell differentiation, and neurodevelopment, but how gene-specific and adaptive regulation by Integrator is achieved remains unclear. Here, we identify two sites on human Integrator subunits 13/14 that serve as binding hubs for sequence-specific transcription factors (TFs) and other transcription effector complexes. When Integrator is attached to paused RNAP2, these hubs are positioned upstream of the transcription bubble, consistent with simultaneous TF-promoter tethering. The TFs co-localize with Integrator genome-wide, increase Integrator abundance on target genes, and co-regulate responsive transcriptional programs. For instance, sensory cilia formation induced by glucose starvation depends on Integrator-TF contacts. Our data suggest TF-mediated promoter recruitment of Integrator as a widespread mechanism for targeted transcription regulation. [Display omitted] • Integrator binds a variety of gene-specific TFs and transcription effector complexes • TF-binding pockets on Integrator are positioned toward the promoter during pausing • Bound TFs co-localize on chromatin with Integrator and co-regulate target genes • Integrator-TF binding is required for transcriptional response to starvation stress Sabath et al. show that Integrator binds various transcription factors (TFs) directly and co-localizes with them on chromatin. TF binding is structurally consistent with Integrator-mediated termination of paused RNAP2. Integrator co-regulates genes with TFs, and Integrator-TF tethering is required for adaptive transcriptional programs such as cellular starvation response and cilia formation. [ABSTRACT FROM AUTHOR]

Background: ZMYND8 (Zinc finger MYND (Myeloid, Nervy and DEAF-1)-type containing 8) has been known to play an important role in tumor regulation in various types of cancer. However, the results of ZMYND8 expression and their clinical significance in hepatocellular carcinoma (HCC) have not yet been published. In the present study, we investigate the expression of ZMYND8 protein and mRNA in HCC and elucidate its prognostic significance. Methods: ZMYND8 protein and mRNA expression in 283 and 234 HCCs were investigated using immunohistochemistry and microarray gene expression profiling data. The relationships between ZMYND8 expression with clinicopathologic features and prognosis of HCC patients were evaluated. Furthermore, we performed the invasion, migration, apoptosis, soft agar formation assay and sphere formation assay in HCC cell lines, and evaluated tumorigenicity in a nude mouse model, after ZMYND8 knockdown. Results: Overexpression of ZMYND8 protein and mRNA was observed in 20.5% and 26.9% of HCC cases, respectively. High ZMYND8 expression showed significant correlations with microvascular invasion, high Edmondson grade, advanced American Joint Committee on Cancer, and increased alpha-fetoprotein level. ZMYND8 mRNA overexpression was an independent prognostic factor for predicting early recurrence as well as short recurrence-free survival (RFS). Downregulation of ZMYND8 reduced migration and invasion of HCC cells, and promoted apoptosis of HCC cells in an in vitro model. In a xenograft nude mouse model, knockdown of ZMYND8 significantly reduced tumor growth. Conclusion: ZMYND8 mRNA overexpression could be a prognostic marker of shorter RFS in HCC patients after curative resection. ZMYND8 might play an important role in the proliferation and progression of HCC and could be a promising candidate for targeted therapy. [ABSTRACT FROM AUTHOR]

Jiewei Chen,1,2,* Jun Liu,1,2,* Xiaoting Chen,1,2,* Yong Li,1,2 Zizi Li,3 Chengchao Shen,1,2 Keming Chen,1,2 Xinke Zhang1,21State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, People’s Republic of China; 2Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, People’s Republic of China; 3Department of Pathology, Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, 519000, People’s Republic of China *These authors contributed equally to this workCorrespondence: Xinke ZhangDepartment of Pathology, Sun Yat-sen University Cancer Center, 651 Dong Feng Road East, Guangzhou 510060, People’s Republic of ChinaTel +86 208 734 2270Email zhangxk@sysucc.org.cnPurpose: ZMYND8 is closely correlated with cancerous proliferation and invasiveness. However, its prognostic value has not been estimated in a nasopharyngeal carcinoma (NPC). The purpose of this study was to elucidate the status of ZMYND8 expression and its prognostic significance in NPCs.Methods: The status of ZMYND8 expression was investigated by immunohistochemistry for NPC samples in the study. The cutoff value of ZMYND8 expression was confirmed in NPCs using ROC-curve analysis. Correlations between ZMYND8 expression and clinicopathological variables and patient prognosis were analyzed by various statistical methods.Results: Our study showed that low expression of ZMYND8 strongly correlated with late T stage in NPCs (P

Both gene repressor (Polycomb-dependent) and activator (Polycombindependent) functions of the Polycomb protein enhancer of zeste homolog 2 (EZH2) are implicated in cancer progression. EZH2 protein can be phosphorylated at various residues, such as threonine 487 (T487), by CDK1 kinase, and such phosphorylation acts as a Polycomb repressive complex 2 (PRC2) suppression "code" to mediate the gene repressor-to-activator switch of EZH2 functions. Here we demonstrate that the histone reader protein ZMYND8 is overexpressed in human clear cell renal cell carcinoma (ccRCC). ZMYND8 binds to EZH2, and their interaction is largely enhanced by CDK1 phosphorylation of EZH2 at T487. ZMYND8 depletion not only enhances Polycombdependent function of EZH2 in hypoxia-exposed breast cancer cells or von Hippel-Lindau (VHL)-deficient ccRCC cells, but also suppresses the FOXM1 transcription program. We further show that ZMYND8 is required for EZH2-FOXM1 interaction and is important for FOXM1-dependent matrix metalloproteinase (MMP) gene expression and EZH2-mediated migration and invasion of VHL-deficient ccRCC cells. Our results identify a previously uncharacterized role of the chromatin reader ZMYND8 in recognizing the PRC2-inhibitory phosphorylation "code" essential for the Polycomb-dependent to -independent switch of EZH2 functions. They also reveal an oncogenic pathway driving cell migration and invasion in hypoxia-inducible factor-activated (hypoxia or VHL-deficient) cancer. [ABSTRACT FROM AUTHOR]

BACKGROUND: Zinc finger MYND (Myeloid, Nervy and DEAF-1)-type containing 8 (ZMYND8) is closely correlated with tumor proliferation and invasiveness. However, its prognostic value has not been estimated in colorectal cancer (CRC). OBJECTIVE: We aimed to elucidate the prognostic significance of ZMYND8 expression and the pN and pM classification supplemented by its expression in CRCs. METHODS: The candidate gene ZMYND8 is identified by TCGA database and GEO database, and then we retrospectively evaluated the status and prognostic significance of ZMYND8 expression of 174 patients with CRC. RESULTS: Online data showed high expression of ZMYND8 is closely correlated with worse overall survival. Our study revealed high expression of ZMYND8 in CRC patients was significantly associated with worse overall and disease-free survival (P < 0.05), and was an independently adverse prognostic factor for overall survival (P < 0.001) and disease-free survival (P = 0.001) by univariate and multivariate analysis. C-index to combined prognostic model containing the pN, pM classification supplemented by the status of ZMYND8 expression showed improved predictive ability comparing with the pN and pM classification model (C-index of 0.597 vs. 0.545, respectively). CONCLUSION: The combined prognostic model could improve the ability to determine the clinical outcome of patients with CRC. [ABSTRACT FROM AUTHOR]

Accumulating evidences indicate the involvement of epigenetic deregulations in cancer. While some epigenetic regulators with aberrant functions in cancer are targeted for improving therapeutic outcome in patients, reinstating the functions of tumor-suppressor-like epigenetic regulators might further potentiate anti-cancer therapies. Epigenetic reader zinc-finger MYND-type-containing 8 (ZMYND8) has been found to be endowed with multiple anti-cancer functions like inhibition of tumor cell migration and proliferation. Here, we report another novel tumor suppressor role of ZMYND8 as an inducer of differentiation in breast cancer cells, by upregulating differentiation genes. Interestingly, we also demonstrated that ZMYND8 mediates all its anti-tumor roles through a common dual-histone mark binding to H4K16Ac and H3K36Me2. We validated these findings by both biochemical and biophysical analyses. Furthermore, we also confirmed the differentiation-inducing potential of ZMYND8 in vivo, using 4T1 murine breast cancer model in Balb/c mice. Differentiation therapy holds great promise in cancer therapy, since it is non-toxic and makes the cancer cells therapy-sensitive. In this scenario, we propose epigenetic reader ZMYND8 as a potential therapeutic candidate for differentiation therapy in breast cancer. [ABSTRACT FROM AUTHOR]

Zinc finger myeloid, nervy, and deformed epidermal autoregulatory factor 1-type containing 8 (Zinc finger MYND-type containing 8, ZMYND8) is a transcription factor, a histone H3-interacting protein, and a putative chromatin reader/effector that plays an essential role in regulating transcription during normal cellular growth. Mutations and altered expression of ZMYND8 are associated with the development and progression of cancer. Increased expression of ZMYND8 is linked to breast, prostate, colorectal, and cervical cancers. It exerts pro-oncogenic effects in breast and prostate cancers, and it promotes angiogenesis in zebrafish, as well as in breast and prostate cancers. In contrast, downregulation of ZMYND8 is also reported in breast, prostate, and nasopharyngeal cancers. ZMYND8 acts as a tumor suppressor in breast and prostate cancers, and it inhibits tumor growth by promoting differentiation; inhibiting proliferation, cell-cycle progression, invasiveness, and metastasis; and maintaining the epithelial phenotype in various types of cancers. These data together suggest that ZMYND8 is important in tumorigenesis; however, the existing data are contradictory. More studies are necessary to clarify the exact role of ZMYND8 in tumorigenesis. In the future, regulation of expression/activity of ZMYND8 and/or its binding partners may become useful in treating cancer.

NuRD (nucleosome remodeling and histone deacetylase) is a versatile multi-protein complex with roles in transcription regulation and the DNA damage response. Here, we show that ZMYND8 bridges NuRD to a number of putative DNA-binding zinc finger proteins. The MYND domain of ZMYND8 directly interacts with PPPLΦ motifs in the NuRD subunit GATAD2A. Both GATAD2A and GATAD2B exclusively form homodimers and define mutually exclusive NuRD subcomplexes. ZMYND8 and NuRD share a large number of genome-wide binding sites, mostly active promoters and enhancers. Depletion of ZMYND8 does not affect NuRD occupancy genome-wide and only slightly affects expression of NuRD/ZMYND8 target genes. In contrast, the MYND domain in ZMYND8 facilitates the rapid, poly(ADP-ribose)-dependent recruitment of GATAD2A/NuRD to sites of DNA damage to promote repair by homologous recombination. Thus, these results show that a specific substoichiometric interaction with a NuRD subunit paralogue provides unique functionality to distinct NuRD subcomplexes.

Despite Bisphenol-A (BPA) being subject to extensive study, a thorough understanding of molecular mechanism remains elusive. Here we show that using weighted gene correlation network analysis (WGCNA), which takes advantage of a graph theoretical approach to understanding correlations amongst genes and grouping genes into modules that typically have co-ordinated biological functions and regulatory mechanisms, that despite some commonality in altered genes, there is minimal overlap between BPA and estrogen in terms of network topology. We confirmed previous findings that ZNF217 and TFAP2C are involved in the estrogen pathway, and are implicated in BPA as well, although for BPA they appear to be active in the absence of canonical estrogen-receptor driven gene expression. Furthermore, our study suggested that PADI4 and RACK7/ZMYNDB8 may be involved in the overlap in gene expression between estradiol and BPA. Lastly, we demonstrated that even at low doses there are unique transcription factors that appear to be driving the biology of BPA, such as SREBF1. Overall, our data is consistent with other reports that BPA leads to subtle gene changes rather than profound aberrations of a conserved estrogen signaling (or other) pathways.

Despite Bisphenol-A (BPA) being subject to extensive study, a thorough understanding of molecular mechanism remains elusive. Here we show that using weighted gene correlation network analysis (WGCNA), which takes advantage of a graph theoretical approach to understanding correlations amongst genes and grouping genes into modules that typically have co-ordinated biological functions and regulatory mechanisms, that despite some commonality in altered genes, there is minimal overlap between BPA and estrogen in terms of network topology. We confirmed previous findings that ZNF217 and TFAP2C are involved in the estrogen pathway, and are implicated in BPA as well, although for BPA they appear to be active in the absence of canonical estrogen-receptor driven gene expression. Furthermore, our study suggested that PADI4 and RACK7/ZMYNDB8 may be involved in the overlap in gene expression between estradiol and BPA. Lastly, we demonstrated that even at low doses there are unique transcription factors that appear to be driving the biology of BPA, such as SREBF1. Overall, our data is consistent with other reports that BPA leads to subtle gene changes rather than profound aberrations of a conserved estrogen signaling (or other) pathways. [ABSTRACT FROM AUTHOR]

Our genetic information is organized into chromatin, which consists of histones and proteins involved in regulating DNA compaction, accessibility and function. Chromatin is decorated by histone modifications, which provide signals that coordinate DNA-based processes including transcription and DNA damage response (DDR) pathways. A major signal involved in these processes is acetylation, which when attached to lysines within proteins, including histones, can be recognized and read by bromodomain-containing proteins. We recently identified the bromodomain protein ZMYND8 (also known as RACK7 and PRKCBP1) as a critical DNA damage response factor involved in regulating transcriptional responses and DNA repair activities at DNA double-strand breaks. Other studies have further defined the molecular details for how ZMYND8 interacts with chromatin and other chromatin modifying proteins to exert its DNA damage response functions. ZMYND8 also plays essential roles in regulating transcription during normal cellular growth, perturbation of which promotes cellular processes involved in cancer initiation and progression. In addition to acetylation, histone methylation and demethylase enzymes have emerged as important regulators of ZMYND8. Here we discuss our current understanding of the molecular mechanisms that govern ZMYND8 function within chromatin, highlighting the importance of this protein for genome maintenance both during the DDR and in cancer. [ABSTRACT FROM AUTHOR]

All trans retinoic acid (ATRA), an active vitamin-A derivative, has been shown to regulate gene expression program and thus imparts anti-proliferative activity to cancer cells. Previously, we identified a dual histone reader ZMYND8 (zinc finger MYND (Myeloid, Nervy and DEAF-1)-type containing 8), to be a novel target of ATRA. In the present study, we attempted to decipher the detail mechanism of its transcription regulation. ATRA can reprogram the epigenetic landscape in the upstream regulatory region of ZMYND8 thereby promoting its expression. Interestingly, there is a unique H3K27Me3 to H3K27Ac switch upon ATRA-treatment. We show here that ATRA causes dynamic changes in recruitment of transcription factor YY1 in concert with HDAC1 at ZMYND8 promoter. Further, we show that ATRA treatment triggers an anti-proliferative activity in cancer cells through regulation of ZMYND8 expression. Subsequently, in 4T1-induced syngenic tumor mouse model, ATRA injection caused significant upregulation of ZMYND8. Overall our findings highlight a novel mechanism underlying ATRA-mediated changes in ZMYND8 expression which, in turn, activates the anti-proliferative program in a cancer cell. Thus, histone reader mediated modulation of epigenetic language could play a significant role in retinoid based therapeutic strategy which is well exploited to combat tumor growth. [ABSTRACT FROM AUTHOR]

Summary NuRD (nucleosome remodeling and histone deacetylase) is a versatile multi-protein complex with roles in transcription regulation and the DNA damage response. Here, we show that ZMYND8 bridges NuRD to a number of putative DNA-binding zinc finger proteins. The MYND domain of ZMYND8 directly interacts with PPPLΦ motifs in the NuRD subunit GATAD2A. Both GATAD2A and GATAD2B exclusively form homodimers and define mutually exclusive NuRD subcomplexes. ZMYND8 and NuRD share a large number of genome-wide binding sites, mostly active promoters and enhancers. Depletion of ZMYND8 does not affect NuRD occupancy genome-wide and only slightly affects expression of NuRD/ZMYND8 target genes. In contrast, the MYND domain in ZMYND8 facilitates the rapid, poly(ADP-ribose)-dependent recruitment of GATAD2A/NuRD to sites of DNA damage to promote repair by homologous recombination. Thus, these results show that a specific substoichiometric interaction with a NuRD subunit paralogue provides unique functionality to distinct NuRD subcomplexes. [ABSTRACT FROM AUTHOR]

How chromatin shapes pathways that promote genome-epigenome integrity in response to DNA damage is an issue of crucial importance. We report that human bromodomain (BRD)-containing proteins, the primary "readers" of acetylated chromatin, are vital for the DNA damage response (DDR). We discovered that more than one-third of all human BRD proteins change localization in response to DNA damage. We identified ZMYND8 (zinc finger and MYND [myeloid, Nervy, and DEAF-1] domain containing 8) as a novel DDR factor that recruits the nucleosome remodeling and histone deacetylation (NuRD) complex to damaged chromatin. Our data define a transcription-associated DDR pathway mediated by ZMYND8 and the NuRD complex that targets DNA damage, including when it occurs within transcriptionally active chromatin, to repress transcription and promote repair by homologous recombination. Thus, our data identify human BRD proteins as key chromatin modulators of the DDR and provide novel insights into how DNA damage within actively transcribed regions requires chromatin-binding proteins to orchestrate the appropriate response in concordance with the damage-associated chromatin context. [ABSTRACT FROM AUTHOR]

Purpose: ZMYND8 encodes a multidomain protein that serves as a central interactive hub for coordinating critical roles in transcription regulation, chromatin remodeling, regulation of super-enhancers, DNA damage response and tumor suppression. We delineate a novel neurocognitive disorder caused by variants in the ZMYND8 gene., Methods: An international collaboration, exome sequencing, molecular modeling, yeast two-hybrid assays, analysis of available transcriptomic data and a knockdown Drosophila model were used to characterize the ZMYND8 variants., Results: ZMYND8 variants were identified in 11 unrelated individuals; 10 occurred de novo and one suspected de novo; 2 were truncating, 9 were missense, of which one was recurrent. The disorder is characterized by intellectual disability with variable cardiovascular, ophthalmologic and minor skeletal anomalies. Missense variants in the PWWP domain of ZMYND8 abolish the interaction with Drebrin and missense variants in the MYND domain disrupt the interaction with GATAD2A. ZMYND8 is broadly expressed across cell types in all brain regions and shows highest expression in the early stages of brain development. Neuronal knockdown of the DrosophilaZMYND8 ortholog results in decreased habituation learning, consistent with a role in cognitive function., Conclusion: We present genomic and functional evidence for disruption of ZMYND8 as a novel etiology of syndromic intellectual disability., Competing Interests: Conflict of Interest S.V.M., T.B.P., and M.J.G.S. are employees of GeneDx, Inc. All other authors declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Abstract: Regulation of neuronal gene expression is critical to nervous system development. REST (RE1-silencing transcription factor) regulates neuronal gene expression through interacting with a group of corepressor proteins including REST corepressors (RCOR). Here we show that Xenopus RCOR2 is predominantly expressed in the developing nervous system. Through a yeast two-hybrid screen, we isolated Xenopus ZMYND8 (Zinc finger and MYND domain containing 8) as an XRCOR2 interacting factor. XRCOR2 and XZMYND8 bind each other in co-immunoprecipitation assays and both of them can function as transcriptional repressors. XZMYND8 is co-expressed with XRCOR2 in the nervous system and overexpression of XZMYND8 inhibits neural differentiation in Xenopus embryos. These data reveal a RCOR2/ZMYND8 complex which might be involved in the regulation of neural differentiation. [Copyright &y& Elsevier]

ZMYND8, an epigenetic regulator, was identified as a common oncogene across various tumors. However, little was reported about the association between ZMYND8 and bladder cancer. Besides, aberrant mechanisms that contribute to abnormal ZMYND8 expressions still remain unclear. In the current study, we first found that ZMYND8 protein levels were significantly elevated in Bca samples versus normal tissues, but not the mRNA levels. We then utilized the Cell Counting Kit-8 (CCK-8) assay, clone formation assay and transwell analysis to confirm that ZMYND8 could remarkably promote the tumor progression in vitro, including growth capacity and migration. Bioinformatic predictive analysis revealed that E3 ubiquitin ligase FBXW7 interacts directly with ZMYND8 and degrades ZMYND8 in a polyubiquitination manner. Low FBXW7 was a hazard factor for promoting and depending on accumulated ZMYND8 proteins to promote Bca progression. Gene set enrichment analysis (GSEA) further indicated that ZMYND8 was notably associated with stemness process, which was well functionally validated. Lastly, ZMYND8 deficiency was observed to inhibit tumor growth of Bca in vivo, revealing a promising translational significance in Bca treatment. In conclusion, our study for the first time provided evidence for a novel mechanism of FBXW7/ZMYND8 axis in Bca, providing therapeutic vulnerability for individualized cancer treatment. [ABSTRACT FROM AUTHOR]

The transformed state in acute leukemia requires gene regulatory programs involving transcription factors and chromatin modulators. Here, we uncover an IRF8-MEF2D transcriptional circuit as an acute myeloid leukemia (AML)-biased dependency. We discover and characterize the mechanism by which the chromatin "reader" ZMYND8 directly activates IRF8 in parallel with the MYC proto-oncogene through their lineage-specific enhancers. ZMYND8 is essential for AML proliferation in vitro and in vivo and associates with MYC and IRF8 enhancer elements that we define in cell lines and in patient samples. ZMYND8 occupancy at IRF8 and MYC enhancers requires BRD4, a transcription coactivator also necessary for AML proliferation. We show that ZMYND8 binds to the ET domain of BRD4 via its chromatin reader cassette, which in turn is required for proper chromatin occupancy and maintenance of leukemic growth in vivo. Our results rationalize ZMYND8 as a potential therapeutic target for modulating essential transcriptional programs in AML. [Display omitted] • IRF8 and MEF2D form a transcriptional circuit to support AML proliferation • A CRISPR screen identifies ZMYND8 as an AML-biased vulnerability • ZMYND8 regulates IRF8 in parallel with MYC via lineage-specific enhancers in AML • ZMYND8 employs its triple reader cassette for enhancer occupancy and cancer growth Uncovering transcriptional addictions in cancer can help guide precision therapeutic intervention. Cao et al. used CRISPR screening to reveal how an acute-myeloid-leukemia-essential IRF8-MEF2D transcriptional circuit can be selectively inhibited by perturbing the reader function of an epigenetic regulator, ZMYND8. [ABSTRACT FROM AUTHOR]

Cholesterol metabolism is tightly associated with colorectal cancer (CRC). Nevertheless, the clinical benefit of statins, the inhibitor of cholesterol biogenesis mevalonate (MVA) pathway, is inconclusive, possibly because of a lack of patient stratification criteria. Here, we describe that YAP-mediated zinc finger MYND-type containing 8 (ZMYND8) expression sensitizes intestinal tumors to the inhibition of the MVA pathway. We show that the oncogenic activity of YAP relies largely on ZMYND8 to enhance intracellular de novo cholesterol biogenesis. Disruption of the ZMYND8-dependent MVA pathway greatly restricts the self-renewal capacity of Lgr5 + intestinal stem cells (ISCs) and intestinal tumorigenesis. Mechanistically, ZMYND8 and SREBP2 drive the enhancer-promoter interaction to facilitate the recruitment of Mediator complex, thus upregulating MVA pathway genes. Together, our results establish that the epigenetic reader ZMYND8 endows YAP-high intestinal cancer with metabolic vulnerability. [Display omitted] • ZMYND8-mediated MVA biogenesis promotes intestinal stemness and tumorigenesis • ZMYND8/SREBP2-coordinated enhancer-promoter interaction activates the MVA pathway • YAP stimulates cholesterol biogenesis via ZMYND8 Pan et al. uncover a metabolic addiction of the MVA pathway in YAP-driven tumors. The identified YAP target gene ZMYND8 interacts with SERBP2 to enable enhancer-promoter communication to upregulate the MVA pathway. These findings provide a rationale to use MVA pathway inhibitors (statins) to treat the tumors with YAP-high activity. [ABSTRACT FROM AUTHOR]

The bromodomain protein zinc finger MYND-type containing 8 (ZMYND8) plays a critical role in human breast cancer. However, the expression and biological function of ZMYND8 in hepatocellular carcinoma (HCC) are poorly understood. In this study, ZMYND8 expression was found to be elevated in HCC based on the cancer genome atlas (TCGA) and gene expression omnibus (GEO) databases. Next, we confirmed that ZMYND8 was frequently overexpressed in HCC tissues compared with adjacent non-tumor tissues. The up-regulated level of ZMYND8 was also observed in HCC cell lines. Elevated ZMYND8 expression was correlated with unfavorable clinicopathological features and poor prognosis of HCC patients. Functionally, ectopic expression of ZMYND8 potentiated the proliferation, migration, and invasion of Hep3B cells. Conversely, ZMYND8 knockdown led to the reduced proliferation and invasiveness of HCCLM3 cells. ZMYND8 silencing restrained the growth of HCCLM3 cells in vivo. Mechanistically, ZMYND8 enhanced glucose consumption, lactate production, and ATP level in HCC cells. Pharmacological inhibition of glycolysis using 2-DG blocked the promoting effects of ZMYND8 on HCC cell proliferation and mobility. Furthermore, hexokinase 2 (HK2), a key enzyme of glycolysis, was identified as the downstream target of ZMYND8 in HCC cells. ZMYND8 promoted HK2 transcription by recruiting bromodomain containing 4 (BRD4) to its promoter. Knockdown of HK2 abrogated the oncogenic functions of ZMYND8 in HCC. Altogether, these data indicated that ZMYND8 promoted the growth and metastasis of HCC by promoting HK2-mediated glycolysis and might serve as a promising biomarker and therapeutic target for HCC. [ABSTRACT FROM AUTHOR]

Zinc finger myeloid, nervy, and deformed epidermal autoregulatory factor 1-type containing 8 (Zinc finger MYND-type containing 8, ZMYND8) is a transcription factor, a histone H3-interacting protein, and a putative chromatin reader/effector that plays an essential role in regulating transcription during normal cellular growth. Mutations and altered expression of ZMYND8 are associated with the development and progression of cancer. Increased expression of ZMYND8 is linked to breast, prostate, colorectal, and cervical cancers. It exerts pro-oncogenic effects in breast and prostate cancers, and it promotes angiogenesis in zebrafish, as well as in breast and prostate cancers. In contrast, downregulation of ZMYND8 is also reported in breast, prostate, and nasopharyngeal cancers. ZMYND8 acts as a tumor suppressor in breast and prostate cancers, and it inhibits tumor growth by promoting differentiation; inhibiting proliferation, cell-cycle progression, invasiveness, and metastasis; and maintaining the epithelial phenotype in various types of cancers. These data together suggest that ZMYND8 is important in tumorigenesis; however, the existing data are contradictory. More studies are necessary to clarify the exact role of ZMYND8 in tumorigenesis. In the future, regulation of expression/activity of ZMYND8 and/or its binding partners may become useful in treating cancer. [ABSTRACT FROM AUTHOR]

Both gene repressor (Polycomb-dependent) and activator (Polycomb-independent) functions of the Polycomb protein enhancer of zeste homolog 2 (EZH2) are implicated in cancer progression. EZH2 protein can be phosphorylated at various residues, such as threonine 487 (T487), by CDK1 kinase, and such phosphorylation acts as a Polycomb repressive complex 2 (PRC2) suppression "code" to mediate the gene repressor-to-activator switch of EZH2 functions. Here we demonstrate that the histone reader protein ZMYND8 is overexpressed in human clear cell renal cell carcinoma (ccRCC). ZMYND8 binds to EZH2, and their interaction is largely enhanced by CDK1 phosphorylation of EZH2 at T487. ZMYND8 depletion not only enhances Polycomb-dependent function of EZH2 in hypoxia-exposed breast cancer cells or von Hippel-Lindau (VHL)-deficient ccRCC cells, but also suppresses the FOXM1 transcription program. We further show that ZMYND8 is required for EZH2-FOXM1 interaction and is important for FOXM1-dependent matrix metalloproteinase ( MMP ) gene expression and EZH2-mediated migration and invasion of VHL-deficient ccRCC cells. Our results identify a previously uncharacterized role of the chromatin reader ZMYND8 in recognizing the PRC2-inhibitory phosphorylation "code" essential for the Polycomb-dependent to -independent switch of EZH2 functions. They also reveal an oncogenic pathway driving cell migration and invasion in hypoxia-inducible factor-activated (hypoxia or VHL-deficient) cancer., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)

Summary Class switch recombination (CSR) is a DNA recombination reaction that diversifies the effector component of antibody responses. CSR is initiated by activation-induced cytidine deaminase (AID), which targets transcriptionally active immunoglobulin heavy chain (Igh) switch donor and acceptor DNA. The 3′ Igh super-enhancer, 3′ regulatory region (3′RR), is essential for acceptor region transcription, but how this function is regulated is unknown. Here, we identify the chromatin reader ZMYND8 as an essential regulator of the 3′RR. In B cells, ZMYND8 binds promoters and super-enhancers, including the Igh enhancers. ZMYND8 controls the 3′RR activity by modulating the enhancer transcriptional status. In its absence, there is increased 3′RR polymerase loading and decreased acceptor region transcription and CSR. In addition to CSR, ZMYND8 deficiency impairs somatic hypermutation (SHM) of Igh , which is also dependent on the 3′RR. Thus, ZMYND8 controls Igh diversification in mature B lymphocytes by regulating the activity of the 3′ Igh super-enhancer. Graphical Abstract Highlights • ZMYND8 is required for GLT of acceptor S regions and Class Switch Recombination • ZMYND8 supports efficient somatic hypermutation of the Igh variable regions • ZMYND8 binds B cell super-enhancers, including the 3′ Igh enhancer • ZMYND8 modulates the transcriptional status and activity of the 3′ Igh enhancer Antibody diversity is essential for the establishment of an effective immune response. Delgado-Benito and Rosen et al. report that diversification of the immunoglobulin heavy chain (Igh) gene in mature B lymphocytes is regulated by the chromatin reader ZMYND8, which binds to and modulates the activity of the 3′ Igh locus super-enhancer. [ABSTRACT FROM AUTHOR]

Although human ZMYND8 has been implicated as a transcriptional co-repressor of multiple targets, global association of ZMYND8 with active genes and enhancer regions predicts otherwise. Here, we report an additional function of ZMYND8 in transcriptional activation through its association with the P-TEFb complex. Biochemical reconstitution analyses show that human ZMYND8, through direct association with CylcinT1, forms a minimal ZMYND8-P-TEFb complex. The importance of ZMYND8 in target gene activation, through P-TEFb complex recruitment, is demonstrated on chromosomally integrated reporter gene as well as native target genes in vivo. Physiologically, we further show that the ZMYND8-P-TEFb complex-mediated transcriptional activation is required for all- trans retinoic acid (ATRA)-mediated differentiation of neuronal precursor cells. Finally, to detail the dual activator and repressor nature, mechanistically we show that, through its putative coiled-coil domain, ZMYND8 forms a homodimer that preferentially associates with the activator P-TEFb complex, whereas the monomer associates with the CHD4 subunit of repressor NuRD complex. • ZMYND8-mediated P-TEFb complex recruitment activates transcription • Differentiation of SH-SH5Y cells requires transcriptional activation by ZMYND8 • ZMYND8 exists as monomer as well as dimer • Preferential association of CHD4 with monomer and P-TEFb with dimer form of ZMYND8 Ghosh et al. report that coiled-coil domain-dependent dimerization of ZMYND8 positively regulates transcription through P-TEFb complex recruitment, whereas monomeric ZMYND8 associates with NuRD complex for transcriptional repression. ZMYND8-mediated P-TEFb complex recruitment is required for target gene activation during retinoic acid-induced differentiation of SH-SY5Y cells. [ABSTRACT FROM AUTHOR]

Summary Malfunctions of the actin binding protein Drebrin have been implicated in various human diseases such as Alzheimer's disease, cognitive impairments, cancer, and digestive disorders, though with poorly understood mechanisms. The ADF-H domain of Drebrin does not contain actin binding and depolymerizing activity. Instead, it binds to a histone marker reader, ZMYND8. Here we present the high-resolution crystal structure of Drebrin ADF-H in complex with the ZMYND8 PHD-BROMO-PWWP tandem, elucidating the mechanistic basis governing the highly specific interaction of the two proteins. The structure reveals that the ZMYND8 PHD-BROMO-PWWP tandem forms a structural supramodule that is necessary for binding to Drebrin ADF-H. Drebrin ADF-H competes with modified histone for binding to ZMYND8. Binding of Drebrin can shuttle ZMYND8 from nucleus to cytoplasm in living cells. Taken together, our study uncovers a non-actin target binding mode for ADF-H domains, and suggests that Drebrin may regulate activities of epigenetic reader ZMYND8 via its cytoplasmic sequestration. [ABSTRACT FROM AUTHOR]

Enhanced migratory potential and invasiveness of cancer cells contribute crucially to cancer progression. These phenotypes are achieved by precise alteration of invasion-associated genes through local epigenetic modifications which are recognized by a class of proteins termed a chromatin reader. ZMYND8 [zinc finger MYND (myeloid, Nervy and DEAF-1)-type containing 8], a key component of the transcription regulatory network, has recently been shown to be a novel reader of H3.1K36Me2/H4K16Ac marks. Through differential gene expression analysis upon silencing this chromatin reader, we identified a subset of genes involved in cell proliferation and invasion/migration regulated by ZMYND8. Detailed analysis uncovered its antiproliferative activity through BrdU incorporation, alteration in the expression of proliferation markers, and cell cycle regulating genes and cell viability assays. In addition, performing wound healing and invasion/migration assays, its anti-invasive nature is evident. Interestingly, epithelial-mesenchymal transition (EMT), a key mechanism of cellular invasion, is regulated by ZMYND8 where we identified its selective enrichment on promoters of CLDN1 / CDH1 genes, rich in H3K36Me2/H4K16Ac marks, leading to their up-regulation. Thus, the presence of ZMYND8 could be implicated in maintaining the epithelial phenotype of cells. Furthermore, syngeneic mice, injected with ZMYND8-overexpressed invasive breast cancer cells, showed reduction in tumor volume and weight. In concert with this, we observed a significant down-regulation of ZMYND8 in invasive ductal and lobular breast cancer tissues compared with normal tissue. Taken together, our study elucidates a novel function of ZMYND8 in regulating EMT and invasion of cancer cells, possibly through its chromatin reader function., (© 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society.)

All trans retinoic acid (ATRA), an active vitamin-A derivative, has been shown to regulate gene expression program and thus imparts anti-proliferative activity to cancer cells. Previously, we identified a dual histone reader ZMYND8 (zinc finger MYND (Myeloid, Nervy and DEAF-1)-type containing 8), to be a novel target of ATRA. In the present study, we attempted to decipher the detail mechanism of its transcription regulation. ATRA can reprogram the epigenetic landscape in the upstream regulatory region of ZMYND8 thereby promoting its expression. Interestingly, there is a unique H3K27Me3 to H3K27Ac switch upon ATRA-treatment. We show here that ATRA causes dynamic changes in recruitment of transcription factor YY1 in concert with HDAC1 at ZMYND8 promoter. Further, we show that ATRA treatment triggers an anti-proliferative activity in cancer cells through regulation of ZMYND8 expression. Subsequently, in 4T1-induced syngenic tumor mouse model, ATRA injection caused significant upregulation of ZMYND8. Overall our findings highlight a novel mechanism underlying ATRA-mediated changes in ZMYND8 expression which, in turn, activates the anti-proliferative program in a cancer cell. Thus, histone reader mediated modulation of epigenetic language could play a significant role in retinoid based therapeutic strategy which is well exploited to combat tumor growth., (Copyright © 2017 Elsevier B.V. All rights reserved.)

How chromatin shapes pathways that promote genome-epigenome integrity in response to DNA damage is an issue of crucial importance. We report that human bromodomain (BRD)-containing proteins, the primary "readers" of acetylated chromatin, are vital for the DNA damage response (DDR). We discovered that more than one-third of all human BRD proteins change localization in response to DNA damage. We identified ZMYND8 (zinc finger and MYND [myeloid, Nervy, and DEAF-1] domain containing 8) as a novel DDR factor that recruits the nucleosome remodeling and histone deacetylation (NuRD) complex to damaged chromatin. Our data define a transcription-associated DDR pathway mediated by ZMYND8 and the NuRD complex that targets DNA damage, including when it occurs within transcriptionally active chromatin, to repress transcription and promote repair by homologous recombination. Thus, our data identify human BRD proteins as key chromatin modulators of the DDR and provide novel insights into how DNA damage within actively transcribed regions requires chromatin-binding proteins to orchestrate the appropriate response in concordance with the damage-associated chromatin context., (© 2015 Gong et al.; Published by Cold Spring Harbor Laboratory Press.)