Search

The histone demethylase KDM6A controls gene expression by the epigenetic regulation of H3K27 methylation and functions in diverse processes, including differentiation, development, and cancer. Here, we investigated the role of KDM6A in prostate cancer. Specific deletion of KDM6A in the adult mouse prostate epithelium strongly inhibited tumor progression initiated by the loss of PTEN. Mechanistically, KDM6A promoted prostate tumorigenesis and lipid metabolism by binding to the SREBP1c promoter to increase SREBP1c transcription. USP7 deubiquitinated KDM6A to increase its expression. KDM6A was significantly upregulated in prostate cancer and positively associated with USP7 expression. Furthermore, targeting KDM6A stability by inhibiting USP7 in conditional knockout mice and xenograft models markedly suppressed prostate cancer growth and significantly enhanced KDM6A inhibitor efficacy. Collectively, these findings indicate that KDM6A regulates prostate lipid metabolism and is essential for prostate tumorigenesis initiated by PTEN loss. Targeting USP7/KDM6A could be a valuable strategy to ameliorate prostate cancer progression and therapeutic resistance. Significance: These findings show that KDM6A supports prostate tumorigenesis by promoting SREBP1c-mediated lipid metabolism, proposing targeting the USP7/KDM6A axis as a therapeutic strategy for treating prostate cancer.

Background Previous studies have shown that the Ecotropic Viral Integration Site 2A (EVI2A) could serve as a meaningful marker in many diseases, yet its potential biological function and mechanism in kidney renal clear cell (KIRC) carcinoma have not been investigated. Methods TCGA and GEO databases were used for EVI2A gene expression and pan-cancer analysis. We used Kaplan-Meier (K-M) analysis, receiver operating characteristic (ROC) curves, and nomogram to assess the clinical utility of EVI2A. In parallel, we evaluated the immune relevance of the gene by tumor microenvironment (TME), Tumor Immune Single-cell Hub (TISCH), immune checkpoint, and immunotherapy sensitivity analysis. Finally, the expression of this gene was verified in vitro assay and further verified the biological behavior in renal clear cell carcinoma by cell function experiments. Results EVI2A expression in KIRC were upregulated and associated with patients’ tumor grade, T /N/M stage. The diagnostic AUC of EVI2A was 0.906. Its high expression indicated poor overall survival and progression-free survival in KIRC patients. Both GO, and KEGG analysis indicated significant correlations between EVI2A expression and immunity. The higher the EVI2A expression, the higher the TME scores. Furthermore, EVI2A was positively correlated with Tfh cells, CD4 memory T cells and CD8 + T cells. Patients with high expression of EVI2A are more sensitive to PD-1/CTLA-4 and tyrosine kinase inhibitors. In vitro experiments showed that the knockdown of EVI2A reduced KIRC cell proliferation, invasion, and migration. Conclusion Comprehensive analysis indicated that EVI2A may be a potential meaningful biomarker and novel target for KIRC intervention.

Supplementary Data from Targeting KDM6A Suppresses SREBP1c-Dependent Lipid Metabolism and Prostate Tumorigenesis

The histone demethylase KDM6A controls gene expression by the epigenetic regulation of H3K27 methylation and functions in diverse processes, including differentiation, development, and cancer. Here, we investigated the role of KDM6A in prostate cancer. Specific deletion of KDM6A in the adult mouse prostate epithelium strongly inhibited tumor progression initiated by the loss of PTEN. Mechanistically, KDM6A promoted prostate tumorigenesis and lipid metabolism by binding to the SREBP1c promoter to increase SREBP1c transcription. USP7 deubiquitinated KDM6A to increase its expression. KDM6A was significantly upregulated in prostate cancer and positively associated with USP7 expression. Furthermore, targeting KDM6A stability by inhibiting USP7 in conditional knockout mice and xenograft models markedly suppressed prostate cancer growth and significantly enhanced KDM6A inhibitor efficacy. Collectively, these findings indicate that KDM6A regulates prostate lipid metabolism and is essential for prostate tumorigenesis initiated by PTEN loss. Targeting USP7/KDM6A could be a valuable strategy to ameliorate prostate cancer progression and therapeutic resistance.Significance:These findings show that KDM6A supports prostate tumorigenesis by promoting SREBP1c-mediated lipid metabolism, proposing targeting the USP7/KDM6A axis as a therapeutic strategy for treating prostate cancer.

Background Combined small cell lung cancer (CSCLC) is a subtype of small cell lung cancer (SCLC) which contains both components of SCLC and non-small cell lung cancer (NSCLC). The prognostic outcomes and treatment strategy of it are still unclear. A large-scale retrospective study was performed to investigate proper treatments for CSCLC. Methods All cases of CSCLC were identified from the SEER database during the period of 2004-2016. Clinical characteristics, first-line treatments, surgical procedures and survival data including overall survival (OS) and cancer-specific survival (CSS) were analyzed. Results A total of 37,639 SCLC patients were identified. CSCLC accounted for 2.1% (784/37,639). The mean age of CSCLC cohort is 67.3±9.9 years old. Male and white ethnicity patients were accounted for larger proportions (55.7% and 80.4%). The oncological characteristics of CSCLC were consistent with SCLC that most of patients were diagnosed as higher grade and advanced stages. The prognosis of CSCLC was better than SCLC but worse than NSCLC in IA-IIIA stages. No difference was observed in IIIB-IV. Surgery was beneficial in IA-IB stage CSCLC. Adjuvant chemotherapy seemed to have few effects on early stage patients. Trimodality treatment could significantly improve OS in IIA-IIIA CSCLC patients. Chemotherapy-based treatment is predominant choice in advanced stage patients. Conclusions CSCLC is a rare and special subtype of SCLC. It has better survival outcome than non-CSCLC in early stage. Surgical treatment is crucial in early stage of CSCLC. Prognostic improvement might be achieved from trimodality treatment in stage IIA-IIIA. Chemotherapy-based treatments should be considered in advanced stage. The effect of surgical treatments in advanced stage patients should be further investigated.

The histone demethylase KDM4B functions as a key co-activator for the androgen receptor (AR) and plays a vital in multiple cancers through controlling gene expression by epigenetic regulation of H3K9 methylation marks. Constitutively active androgen receptor confers anti-androgen resistance in advanced prostate cancer. However, the role of KDM4B in resistance to next-generation anti-androgens and the mechanisms of KDM4B regulation are poorly defined. Here we found that KDM4B is overexpressed in enzalutamide-resistant prostate cancer cells. Overexpression of KDM4B promoted recruitment of AR to the c-Myc (MYC) gene enhancer and induced H3K9 demethylation, increasing AR-dependent transcription of c-Myc mRNA, which regulates the sensitivity to next-generation AR-targeted therapy. Inhibition of KDM4B significantly inhibited prostate tumor cell growth in xenografts, and improved enzalutamide treatments through suppression of c-Myc. Clinically, KDM4B expression was found upregulated and to correlate with prostate cancer progression and poor prognosis. Our results revealed a novel mechanism of anti-androgen resistance via histone demethylase alteration which could be targeted through inhibition of KDM4B to reduce AR-dependent c-Myc expression and overcome resistance to AR-targeted therapies. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

BACKGROUND: The 8(th) edition staging system for malignant pleural mesothelioma (MPM) has been proposed. The size of tumor is not taken into consideration. We intend to elucidate the prognostic value of the size of MPM and evaluate the current staging system via the data of SEER database. METHODS: All cases of primary MPM were identified and extracted from the SEER database during the period of 2004–2016. The endpoints were overall survival (OS) and cancer-specific survival (CSS) which were analyzed using Kaplan-Meier method. Log-rank test and Cox regression were utilized to identify the prognostic factors. RESULTS: A total of 2,138 patients were included in the primary cohort. The 1-, 3- and 5-year survival rates of MPM were 39.4%, 11.8% and 3.8%. Older, male and advanced stage patients accounted for larger proportion of the cohort. Besides tumor extension, lymph node involvement and metastatic status, tumor size, pathological type and differentiation grade were significant prognostic factors. In the stratified analysis of tumor extension, size is a significant prognostic factor in T2 patients and indicates inferior survival outcomes. Surgery, chemotherapy and radiation can increase both OS and CSS in MPM patients. Triple combination treatments showed a superiority to other treatments. CONCLUSIONS: Tumor size matters in the prognosis of MPM especially in the early stage of MPM patients. The adjusted TNM staging system incorporating tumor size has better accuracy than the 8(th) edition IMIG system. However, some stages had not been fully identified. More cases of early stages are warranted for essential revision.

The DNA damage response (DDR) pathway is a promising target for anticancer therapies. The androgen receptor and myeloblastosis transcription factors have been reported to regulate expression of an overlapping set of DDR genes in prostate cancer cells. Here, we found that histone demethylase JMJD1A regulates expression of a different set of DDR genes largely through c-Myc. Inhibition of JMJD1A delayed the resolution of γ-H2AX foci, reduced the formation of foci containing ubiquitin, 53BP1, BRCA1 or Rad51, and inhibited the reporter activity of double-strand break (DSB) repair. Mechanistically, JMJD1A regulated expression of DDR genes by increasing not only the level but also the chromatin recruitment of c-Myc through H3K9 demethylation. Further, we found that ubiquitin ligase HUWE1 induced the K27-/K29-linked noncanonical ubiquitination of JMJD1A at lysine-918. Ablation of the JMJD1A noncanonical ubiquitination lowered DDR gene expression, impaired DSB repair, and sensitized response of prostate cells to irradiation, topoisomerase inhibitors or PARP inhibitors. Thus, development of agents that target JMJD1A or its noncanonical ubiquitination may sensitize the response of prostate cancer to radiotherapy and possibly also genotoxic therapy.

Post‑translational modifications of histones by histone demethylases have an important role in the regulation of gene transcription and are implicated in cancers. Recently, the family of lysine (K)‑specific demethylase (KDM) proteins, referring to histone demethylases that dynamically regulate histone methylation, were indicated to be involved in various pathways related to cancer development. To date, numerous studies have been conducted to explore the effects of KDMs on cancer growth, metastasis and drug resistance, and a majority of KDMs have been indicated to be oncogenes in both leukemia and solid tumors. In addition, certain KDM inhibitors have been developed and have become the subject of clinical trials to explore their safety and efficacy in cancer therapy. However, most of them focus on hematopoietic malignancy. This review summarizes the effects of KDMs on tumor growth, drug resistance and the current status of KDM inhibitors in clinical trials.

BACKGROUND We previously determined that polyplexes formed by linear H2K peptides were more effective in transfecting tumors in vivo than polyplexes formed by branched H2K4b-20 peptides. Based on trypsin digest and salt displacement studies, the linear H2K polyplexes were less stable than the branched H2K4b-20 polyplexes. Because binding and release of the polymer and DNA from the H2K4b-20 polyplex may account for the ineffectiveness, we investigated whether four-branched histidine-lysine (HK) peptides with varying numbers of amino acids in their branches would be more effective in their ability to increase gene expression in tumors in vivo. METHODS Linear and branched peptides with multiple -KHHK- motifs were synthesized by solid-phase synthesis. The branched H2K4b-20, -18, -14 and 12 peptides had 20, 18, 14 and 12 amino acids in their branches, respectively. These peptides were examined for their ability to carry luciferase-expressing plasmids to human breast cancer xenografts in a mouse model. With gel retardation and in vivo transfection, the incorporation of a targeting ligand and an endosomal lysis peptide into these polyplexes was also examined. A blocking antibody was pre-injected prior to the polyplexes to determine the role of neuropilin 1 in the uptake of these polyplexes by the tumor. The size of the polyplexes was measured by dynamic light scattering. RESULTS Of the four negative surface-charge polyplexes formed by the branched carriers, the H2K4b-14 polyplex was determined to be the most effective plasmid delivery platform to tumors. The incorporation of a targeting ligand and an endosomal lysis peptide into H2K4b-14 polyplexes further enhanced their ability to transfect tumors in vivo. Furthermore, after pre-injecting tumor-bearing mice with a blocking antibody to the neuropilin-1 receptor (NRP-1), there was a marked reduction of tumor gene expression with the modified H2K4b-14 polyplexes, suggesting that NRP-1 mediated their transport into the tumor. CONCLUSIONS The present study established that branched peptides intermediate in length were very efficient in delivering plasmids to tumors in vivo.

Gastric cancer (GC) has one of the highest tumor incidences worldwide. Heat shock protein 70 (HSP70) is highly expressed and plays a critical role in the occurrence, progression, metastasis, poor prognosis, and drug resistance of GC. However, the underlying mechanisms of HSP70 are not clear. To explore the regulatory role of HSP70 in GC, we performed cell counting kit-8 (CCK-8) and EdU staining assays to assess cell proliferation; immunohistochemistry and western blot analyses to assess protein expression; coimmunoprecipitation (Co-IP) assays to assess interactions between two proteins; and immunofluorescence to assess protein expression and localization. HSP70 was highly expressed in clinical samples from patients with GC and indicated a poor prognosis. HSP70 inhibition enhanced the sensitivity of GC cells to thermochemotherapy. Furthermore, we found that S phase kinase-associated protein 2 (Skp2) was highly expressed in GC and correlated with HSP70 in array data from The Cancer Genome Atlas (TCGA). Importantly, HSP70 inhibition promoted Skp2 degradation. Skp2 overexpression abrogated HSP70 inhibition-induced cell cycle arrest, suggesting that the role of HSP70 in GC depends on Skp2 expression. Our results illustrate a possible regulatory mechanism of HSP70 and may provide a therapeutic strategy for overcoming resistance to thermochemotherapy.

Yes‐associated protein (YAP) is a component of the canonical Hippo signaling pathway that is known to play essential roles in modulating organ size, development, and tumorigenesis. Activation or upregulation of YAP1, which contributes to cancer cell survival and chemoresistance, has been verified in different types of human cancers. However, the molecular mechanism of YAP1 upregulation in cancer is still unclear. Here we report that the E3 ubiquitin ligase STUB1 ubiquitinates and destabilizes YAP1, thereby inhibiting cancer cell survival. Low levels of STUB1 expression were correlated with increased protein levels of YAP1 in human gastric cancer cell lines and patient samples. Moreover, we revealed that STUB1 ubiquitinates YAP1 at the K280 site by K48‐linked polyubiquitination, which in turn increases YAP1 turnover and promotes cellular chemosensitivity. Overall, our study establishes YAP1 ubiquitination and degradation mediated by the E3 ligase STUB1 as an important regulatory mechanism in gastric cancer, and provides a rationale for potential therapeutic interventions.

Background Previously, we determined that four‐branched histidine‐lysine (HK) peptides were effective carriers of plasmids and small interfering RNA. In the present study, we compared several branched HK carriers and, in particular, two closely‐related H3K4b and H3K(+H)4b peptides for their ability as carriers of mRNA. The H3K(+H)4b peptide differed from its parent analogue, H3K4b, by only a single histidine in each branch. Methods A series of four‐branched HK peptides with varied sequences was synthesized on a solid‐phase peptide synthesizer. The ability of these peptides to carry mRNA expressing luciferase to MDA‐MB‐231 cells was investigated. With gel retardation and heparin displacement assays, the stability of HK polyplexes was examined. We determined the intracellular uptake of HK polyplexes by flow cytometry and fluorescence microscopy. The size and polydispersity index of the polyplexes in several media were measured by dynamic light scattering. Results MDA‐MB‐231 cells transfected by H3K(+H)4b‐mRNA polyplexes expressed 10‐fold greater levels of luciferase than H3K4b polyplexes. With gel retardation and heparin displacement assays, the H3K(+H)4b polyplexes showed greater stability than H3K4b. Intracellular uptake and co‐localization of H3K(+H)4b polyplexes within acidic endosomes were also significantly increased compared to H3K4b. Similar to H3K(+H)4b, several HK analogues with an additional histidine in the second domain of their branches were effective carriers of mRNA. When combined with DOTAP liposomes, H3K(+H)4b was synergistic in delivery of mRNA. Conclusions H3K(+H)4b was a more effective carrier of mRNA than H3K4b. Mechanistic studies suggest that H3K(+H)4b polyplexes were more stable than H3K4b polyplexes. Lipopolyplexes formed with H3K(+H)4b markedly increased mRNA transfection., Branched HK mRNA polyplexes with one additional histidine in a specific location show marked improvement in their cellular uptake, accumulation within endosomes, as well as their transfection efficiency. Those HK carriers lacking an extra histidine, which form mRNA polyplexes, have decreased stability, resulting in a low transfection.

Post-translational modifications of histones by histone demethylases plays an important role in the regulation of gene transcription and are implicated in cancers. Castrate resistant prostate cancer (CRPC) is often driven by constitutively active androgen receptor and commonly becomes resistant to established hormonal therapy strategies such as enzalutamide as a result. However, the role of KDM1B involved in next generation anti-enzalutamide resistance and the mechanisms of KDM1B regulation are poorly defined. Here, we show that KDM1B is upregulated and correlated with prostate cancer progression and poor prognosis. Downregulation of miR-215 is correlated with overexpression of KDM1B in enzalutamide-resistant prostate cancer cells, which promotes AR-dependent AGR2 transcription and regulates the sensitivity to next generation AR-targeted therapy. Inhibition of KDM1B significantly inhibits prostate tumor growth and improves enzalutamide treatments through AGR2 suppression. Our studies demonstrate inhibition of KDM1B can offer a viable therapeutic option to overcome enzalutamide resistance in tumors with deregulated miR-215-KDM1B-AR-AGR2 signaling axis.

Histidines incorporated into carriers of nucleic acids may enhance the extracellular stability of the nanoparticle, yet aid in the intracellular disruption of the nanoparticle, enabling the release of the nucleic acid. Moreover, protonation of histidines in the endosomes may result in endosomal swelling with subsequent lysis. These properties of histidine are based on its five-member imidazole ring in which the two nitrogen atoms may form hydrogen bonds or act as a base in acidic environments. A wide variety of carriers have integrated histidines or histidine-rich domains, which include peptides, polyethylenimine, polysaccharides, platform delivery systems, viral phages, mesoporous silica particles, and liposomes. Histidine-rich carriers have played key roles in our understanding of the stability of nanocarriers and the escape of the nucleic acids from endosomes. These carriers show great promise and offer marked potential in delivering plasmids, siRNA, and mRNA to their intracellular targets.

The androgen receptor (AR) pathway plays a central role in the development of castration-resistant prostate cancer (CRPC). The histone demethylase JMJD1A has been shown to regulate activities of AR and c-Myc transcription factors and promote prostate cancer progression. Here, we report that JMJD1A protein stability is controlled by the ubiquitin ligase STUB1. High levels of JMJD1A were strongly correlated with low STUB1 levels in human CRPC specimens. STUB1 inhibited AR activity, AR-V7 levels, and prostate cancer cell growth partly through degradation of JMJD1A. Furthermore, the acetyltransferase p300 acetylated JMJD1A at lysine (K) 421, a modification that recruits the BET family member BRD4 to block JMJD1A degradation and promote JMJD1A recruitment to AR targets. Increased levels of both total and K421-acetylated JMJD1A were observed in prostate cancer cells as they developed resistance to the AR antagonist enzalutamide. Treatment of prostate cancer cells with either p300 or BET inhibitors destabilized JMJD1A, and enzalutamide-resistant prostate cancer cells were more sensitive than parental cells to these inhibitors. Together, our findings identify a critical role for acetylation of JMJD1A in regulating JMJD1A stability and AR activity in CRPC. These newly identified mechanisms controlling JMJD1A protein stability provide potential druggable targets to encourage the development of additional therapies for advanced prostate cancer. Significance: Identification of mechanisms regulating JMJD1A protein stability reveals new strategies to destabilize JMJD1A and concomitantly inhibit AR activities as potential prostate cancer therapy.

Background: Prostate cancer is the most commonly diagnosed malignancy and second leading cause of cancer death in American men. The histone demethylase KDM4A is reported to be overexpressed and plays a vital in multiple cancers through controlling gene expression by epigenetic regulation of H3K9 or H3K36 methylation marks. The biological role and mechanism of KDM4A in regulating AR activity in prostate cancer, however, remain to be established. Methods: KDM4A expression in PTEN knockout mouse was determined using western blotting, Real-time PCR and immunohistochemical. Functional assays, such as cell survival, cell colony formation, anchorage-independent growth and a xenograft tumor model were used to determine the oncogenic role of KDM4A in prostate cancer cells. Association of KDM4A with USP1 and the deubiquitination assay were determined by co-immunoprecipitation, immunofluorescent staining and immunoblotting. USP1-KDM4A axis promotes AR-dependent c-Myc expression was further investigated using western blotting, chromatin immunoprecipitation and Real-time PCR. The specific USP1 inhibitor ML323 was used for assessing the role of USP1 in prostate cancer cell survival. Co-expression of KDM4A with USP1 was determined by immunohistochemical staining in 146 prostate cancer tissue samples. Results: Herein, we reported KDM4A expression was upregulation in PTEN knockout mouse prostate tissue. Depletion of KDM4A in prostate cancer cells inhibited their proliferation and survival in vivo and vitro. Further studies reveal that USP1 is a deubiquitinase that regulates KDM4A K48-linked deubiquitin and stability. Interestingly, we found c-Myc was a key downstream effector of USP1-KDM4A/AR axis in driving prostate cancer cell proliferation. Notably, upregulation of KDM4A expression with high USP1 expression were observed in 70% of prostate tumors and inhibition of USP1 promotes prostate cancer cells response to therapeutic agent_enzalutamide. Our studies propose USP1 may be an anti-cancer therapeutic target in prostate cancer. Conclusions: Our findings demonstrate that USP1 deubiquitinates and stabilizes KDM4A, which promotes recruitment of AR to the c-Myc gene enhancer and highlight USP1 potential as an anti-cancer therapeutic target in prostate cancer. Keywords: USP1; Prostate cancer; KDM4A; Deubiquitination; Tumorigenesis

The histone demethylase JMJD1A plays a key functional role in spermatogenesis, sex determination, stem cell renewal, and cancer via removing mono- and di-methyl groups from H3K9 to epigenetically control gene expression. However, its role in prostate cancer progression remains unclear. Here, we found JMJD1A was significantly elevated in prostate cancer tissue compared with matched normal tissue. Ectopic JMJD1A expression in prostate cancer cells promoted proliferation, migration, and invasion in vitro, and tumorigenesis in vivo; JMJD1A knockdown exhibited the opposite effects. Mechanically, we revealed that JMJD1A directly interacted with the Snail gene promoter and regulated its transcriptional activity, promoting prostate cancer progression both in vitro and in vivo. Furthermore, we found that JMJD1A transcriptionally activated Snail expression via H3K9me1 and H3K9me2 demethylation at its special promoter region. In summary, our studies reveal JMJD1A plays an important role in regulating proliferation and progression of prostate cancer cells though Snail, and thus highlight JMJD1A as potential therapeutic target for advanced prostate cancer. Implications: Our studies identify that JMJD1A promotes the proliferation and progression of prostate cancer cells through enabling Snail transcriptional activation, and thus highlight JMJD1A as potential therapeutic target for advanced prostate cancer.

The forkhead box A1 (FOXA1), one of the forkhead class of DNA-binding proteins, functions as a transcription factor and plays a vital role in cellular control of embryonic development and cancer progression. Downregulation of FOXA1 has reported in several types of cancer, which contributes to cancer cell survival and chemoresistance. However, the mechanism for FOXA1 downregulation in cancer remains unclear. Here, we report that the ubiquitination enzyme zinc finger protein 91 (ZFP91) ubiquitinates and destabilizes FOXA1, which promotes cancer cell growth. High level of ZFP91 expression correlates with low level of FOXA1 protein in human gastric cancer (GC) cell lines and patient samples. Furthermore, ZFP91 knockdown reduces FOXA1 polyubiquitination, which decreases FOXA1 turnover and enhances cellular sensitivity to chemotherapy. Taken together, our findings reveal ZFP91-FOXA1 axis plays an important role in promoting GC progression and provides us a potential therapeutic intervention in the treatment of GC.

Formation of the androgen receptor splicing variant 7 (AR-V7) is one of the major mechanisms by which resistance of prostate cancer to androgen deprivation therapy occurs. The histone demethylase JMJD1A (Jumonji domain containing 1A) functions as a key coactivator for AR by epigenetic regulation of H3K9 methylation marks. Here, we describe a role for JMJD1A in AR-V7 expression. While JMJD1A knockdown had no effect on full-length AR (AR-FL), it reduced AR-V7 levels in prostate cancer cells. Reexpression of AR-V7 in the JMJD1A-knockdown cells elevated expression of select AR targets and partially rescued prostate cancer cell growth in vitro and in vivo. The AR-V7 protein level correlated positively with JMJD1A in a subset of human prostate cancer specimens. Mechanistically, we found that JMJD1A promoted alternative splicing of AR-V7 through heterogeneous nuclear ribonucleoprotein F (HNRNPF), a splicing factor known to regulate exon inclusion. Knockdown of JMJD1A or HNRNPF inhibited splicing of AR-V7, but not AR-FL, in a minigene reporter assay. JMJD1A was found to interact with and promote the recruitment of HNRNPF to a cryptic exon 3b on AR pre-mRNA for the generation of AR-V7. Taken together, the role of JMJD1A in AR-FL coactivation and AR-V7 alternative splicing highlights JMJD1A as a potentially promising target for prostate cancer therapy.

Castration-resistant prostate cancer (CRPC) is the major cause of death for prostate cancer (PCa) patients. Re-activation of androgen receptor (AR) activity during androgen-deprivation therapy is believed to underlie CRPC development. We have found that histone demethylase JMJD1A primarily regulates AR and c-Myc activity and thus plays a key role in promoting PCa cell proliferation or survival. Unfortunately, specific JMJD1A inhibitors are not yet available. Here, we identified several post-translational modifications of JMJD1A by performing the JMJD1A immunoprecipitation and mass spectrometry analysis. These modifications include the canonical ubiquitination that targets JMJD1A for proteasome-dependent degradation, non-canonical ubiquitination that enhances the recruitment of co-activators, as well as those that can regulate these ubiquitination events. We also found that these modifications could be manipulated by commercially available inhibitors, to reduce the JMJD1A protein level and prostate cancer cell growth. Thus, targeting the JMJD1A modifications may serve as an alternative means to inhibit JMJD1A activity for the anti-PCa therapy. Note: This abstract was not presented at the meeting. Citation Format: Songhui Xu, Lingling Fan, Xiaolu Cui, Fengbo Zhang, Arif Hussain, Ladan Fazli, Martin Gleave, Jianfei Qi. Post-translational modifications of histone demethylase JMJD1A in prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4389.