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Inactivation of phosphatase and tensin homolog (PTEN) is prevalent in human prostate cancer and causes high-grade adenocarcinoma with a long latency. Cancer-associated fibroblasts (CAFs) play a pivotal role in tumor progression, but it remains elusive whether and how PTEN-deficient prostate cancers reprogram CAFs to overcome the barriers for tumor progression. Here, we report that PTEN deficiency induced Kruppel-like factor 5 (KLF5) acetylation and that interruption of KLF5 acetylation orchestrated intricate interactions between cancer cells and CAFs that enhance FGF receptor 1 (FGFR1) signaling and promote tumor growth. Deacetylated KLF5 promoted tumor cells to secrete TNF-[alpha], which stimulated inflammatory CAFs to release FGF9. CX3CR1 inhibition blocked FGFR1 activation triggered by FGF9 and sensitized PTEN- deficient prostate cancer to the AKT inhibitor capivasertib. This study reveals the role of KLF5 acetylation in reprogramming CAFs and provides a rationale for combined therapies using inhibitors of AKT and CX3CR1., Introduction Prostate cancer is the most common cancer and the second leading cause of cancer-related death in men in the United States (1). Most prostate cancers are localized and androgen [...]

Emerging evidence has linked the dysregulation of [N.sup.6]-methyladenosine ([m.sup.6] A) modification to inflammation and inflammatory diseases, but the underlying mechanism still needs investigation. Here, we found that high levels of [m.sup.6]A modification in a variety of hyperinflammatory states are p65-dependent because Wilms tumor 1-associated protein (WTAP), a key component of the 'writer' complex, is transcriptionally regulated by p65, and its overexpression can lead to increased levels of [m.sup.6]A modification. Mechanistically, upregulated WTAP is more prone to phase separation to facilitate the aggregation of the writer complex to nuclear speckles and the deposition of [m.sup.6]A marks on transcriptionally active inflammatory transcripts, thereby accelerating the proinflammatory response. Further, a myeloid deficiency in WTAP attenuates the severity of LPS-induced sepsis and DSS-induced IBD. Thus, the proinflammatory effect of WTAP is a general risk- increasing mechanism, and interrupting the assembly of the [m.sup.6]A writer complex to reduce the global [m.sup.6]A levels by targeting the phase separation of WTAP may be a potential and promising therapeutic strategy for alleviating hyperinflammation., Introduction Inflammation is usually a physiological healing response that is triggered by noxious stimuli and conditions such as infection and tissue injury (1). Moderate inflammation is essential for pathogen clearance, [...]

A growing body of research has identified circadian-rhythm disruption as a risk factor for metabolic health. However, the underlying biological basis remains complex, and complete molecular mechanisms are unknown. There is emerging evidence from animal and human research to suggest that the expression of core circadian genes, such as circadian locomotor output cycles kaput gene (CLOCK), brain and muscle ARNT-Like 1 gene (BMAL1), period (PER), and cyptochrome (CRY), and the consequent expression of hundreds of circadian output genes are integral to the regulation of cellular metabolism. These circadian mechanisms represent potential pathophysiological pathways linking circadian disruption to adverse metabolic health outcomes, including obesity, metabolic syndrome, and type 2 diabetes. Here, we aim to summarize select evidence from in vivo animal models and compare these results with epidemiologic research findings to advance understanding of existing foundational evidence and potential mechanistic links between circadian disruption and altered clock gene expression contributions to metabolic health-related pathologies. Findings have important implications for the treatment, prevention, and control of metabolic pathologies underlying leading causes of death and disability, including diabetes, cardiovascular disease, and cancer., Introduction The daily routines of life on earth are bound to the patterns of the natural environment, leading to the evolution of circadian rhythms in nearly all organisms (1). In [...]

Copy number variation (CNV) at 7q11.23 causes Williams-Beuren syndrome (WBS) and 7q microduplication syndrome (7Dup), neurodevelopmental disorders (NDDs) featuring intellectual disability accompanied by symmetrically opposite neurocognitive features. Although significant progress has been made in understanding the molecular mechanisms underlying 7q11.23- related pathophysiology, the propagation of CNV dosage across gene expression layers and their interplay remains elusive. Here we uncovered 7q11.23 dosage-dependent symmetrically opposite dynamics in neuronal differentiation and intrinsic excitability. By integrating transcriptomics, translatomics, and proteomics of patient-derived and isogenic induced neurons, we found that genes related to neuronal transmission follow 7q11.23 dosage and are transcriptionally controlled, while translational factors and ribosomal genes are posttranscriptionally buffered. Consistently, we found phosphorylated RPS6 (p-RPS6) downregulated in WBS and upregulated in 7Dup. Surprisingly, p-4EBP was changed in the opposite direction, reflecting dosage- specific changes in total 4EBP levels. This highlights different dosage-sensitive dyregulations of the mTOR pathway as well as distinct roles of p-RPS6 and p-4EBP during neurogenesis. Our work demonstrates the importance of multiscale disease modeling across molecular and functional layers, uncovers the pathophysiological relevance of ribosomal biogenesis in a paradigmatic pair of NDDs, and uncouples the roles of p-RPS6 and p-4EBP as mechanistically actionable relays in NDDs., Introduction With over a thousand associated genes and an increasing number of polygenic risk variants, neurodevelopmental disorders (NDDs), in particular autism spectrum disorder (ASD) and intellectual disability (ID), continue to [...]

Splicing factor mutations are common in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), but how they alter cellular functions is unclear. We show that the pathogenic [SRSF2.sup.P95H/+] mutation disrupts the splicing of mitochondrial mRNAs, impairs mitochondrial complex I function, and robustly increases mitophagy. We also identified a mitochondrial surveillance mechanism by which mitochondrial dysfunction modifies splicing of the mitophagy activator PINK1 to remove a poison intron, increasing the stability and abundance of PINK1 mRNA and protein. [SRSF2.sup.P95H]-induced mitochondrial dysfunction increased PINK1 expression through this mechanism, which is essential for survival of [SRSF2.sup.P95H/+] cells. Inhibition of splicing with a glycogen synthase kinase 3 inhibitor promoted retention of the poison intron, impairing mitophagy and activating apoptosis in [SRSF2.sup.P95H/+] cells. These data reveal a homeostatic mechanism for sensing mitochondrial stress through PINK1 splicing and identify increased mitophagy as a disease marker and a therapeutic vulnerability in [SRSF2.sup.P95H] mutant MDS and AML., Introduction Myelodysplastic syndrome (MDS) is a clonal hematopoietic disorder characterized by hyperproliferative bone marrow, dysplastic hematopoietic cells, peripheral cytopenias, and high risk of progression to acute myeloid leukemia (AML). Recurrent [...]

Cancer cells exhibit heightened secretory states that drive tumor progression. Here, we identified a chromosome 3q amplicon that serves as a platform for secretory regulation in cancer. The 3q amplicon encodes multiple Golgi-resident proteins, including the scaffold Golgi integral membrane protein 4 (GOLIM4) and the ion channel ATPase secretory pathway [Ca.sup.2+] transporting 1 (ATP2C1). We show that GOLIM4 recruited ATP2C1 and Golgi phosphoprotein 3 (GOLPH3) to coordinate [Ca.sup.2+]-dependent cargo loading, Golgi membrane bending, and vesicle scission. GOLIM4 depletion disrupted the protein complex, resulting in a secretory blockade that inhibited the progression of 3q-amplified malignancies. In addition to its role as a scaffold, GOLIM4 maintained intracellular manganese (Mn) homeostasis by binding excess Mn in the Golgi lumen, which initiated the routing of Mn-bound GOLIM4 to lysosomes for degradation. We show that Mn treatment inhibited the progression of multiple types of 3q-amplified malignancies by degrading GOLIM4, resulting in a secretory blockade that interrupted prosurvival autocrine loops and attenuated prometastatic processes in the tumor microenvironment. As it potentially underlies the selective activity of Mn against 3q-amplified malignancies, ATP2C1 coamplification increased Mn influx into the Golgi lumen, resulting in a more rapid degradation of GOLIM4. These findings show that functional cooperativity between coamplified genes underlies heightened secretion and a targetable secretory addiction in 3q-amplified malignancies., Introduction In one working hypothesis, cancer cells are the primary architects of the tumor microenvironment (1). Despite a large body of preclinical evidence supporting their antitumor activities (1), strategies to [...]

STING agonists can reprogram the tumor microenvironment to induce immunological clearance within the central nervous system. Using multiplexed sequential immunofluorescence (SeqIF) and the Ivy Glioblastoma Atlas, STING expression was found in myeloid populations and in the perivascular space. The STING agonist 8803 increased median survival in multiple preclinical models of glioblastoma, including QPP8, an immune checkpoint blockade-resistant model, where 100% of mice were cured. Ex vivo flow cytometry profiling during the therapeutic window demonstrated increases in myeloid tumor trafficking and activation, alongside enhancement of [CD8.sup.+] T cell and NK effector responses. Treatment with 8803 reprogrammed microglia to express costimulatory CD80/CD86 and iNOS, while decreasing immunosuppressive CD206 and arginase. In humanized mice, where tumor cell STING is epigenetically silenced, 8803 therapeutic activity was maintained, further attesting to myeloid dependency and reprogramming. Although the combination with a STAT3 inhibitor did not further enhance STING agonist activity, the addition of anti-PD-1 antibodies to 8803 treatment enhanced survival in an immune checkpoint blockade-responsive glioma model. In summary, 8803 as a monotherapy demonstrates marked in vivo therapeutic activity, meriting consideration for clinical translation., Introduction The prognosis of glioblastoma patients is poor, with an approximate median overall survival of 21 months (1). Whereas radiation and chemotherapy are standard treatments at the time of diagnosis, [...]

Clear cell renal cell carcinoma (ccRCC) is an aggressive cancer driven by VHL loss and aberrant HIF-2[alpha] signaling. Identifying means to regulate HIF-2[alpha] thus has potential therapeutic benefit. Acetyl- CoA synthetase 2 (ACSS2) converts acetate to acetyl-CoA and is associated with poor patient prognosis in ccRCC. Here we tested the effects of ACSS2 on HIF-2[alpha] and cancer cell metabolism and growth in ccRCC models and clinical samples. ACSS2 inhibition reduced HIF-2[alpha] levels and suppressed ccRCC cell line growth in vitro, in vivo, and in cultures of primary ccRCC patient tumors. This treatment reduced glycolytic signaling, cholesterol metabolism, and mitochondrial integrity, all of which are consistent with loss of HIF-2[alpha]. Mechanistically, ACSS2 inhibition decreased chromatin accessibility and HIF- 2[alpha] expression and stability. While HIF-2[alpha] protein levels are widely regulated through pVHL-dependent proteolytic degradation, we identify a potential pVHLindependent pathway of degradation via the E3 ligase MUL1. We show that MUL1 can directly interact with HIF-2[alpha] and that overexpression of MUL1 decreased HIF-2[alpha] levels in a manner partially dependent on ACSS2. These findings identify multiple mechanisms to regulate HIF-2[alpha] stability and ACSS2 inhibition as a strategy to complement HIF-2[alpha]-targeted therapies and deplete pathogenically stabilized HIF-2[alpha]., Introduction Clear cell renal cell carcinoma (ccRCC) is the most abundant subtype of kidney cancer, accounting for 75% of all cases (1). In ccRCC, a deregulated hypoxia transcriptional response is [...]

The Xuefeng black bone chicken (XFBC) represents an important poultry genetic resource. However, the darkness in breast muscle is heterogeneous. The molecular genetic mechanisms underlying melanogenesis of breast muscle in XFBC remains unclear. This study used RNA-seq to compare the difference in transcriptome between hyperpigmentation and hypopigmentation of breast muscle. Six cDNA libraries were constructed for hyperpigmentation and hypopigmentation groups in XFBC. We identified 395 differently expressed genes (DEGs) between hyperpigmentation and hypopigmentation group (P < 0.05, |[log.sub.2]FC|[greater than or equal to]1). Gene ontology (GO) enrichment and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated several differentially enriched biological functions and pathways involved in melanogenesis of the breast muscle. Gene set enrichment analysis (GSEA) GO analysis identified two significant gene sets, including the pathways of pigment metabolic process and transmembrane receptor protein tyrosine kinase activity. GSEA-KEGG analysis identified the process of tyrosine metabolism and several genes related with melanogenesis in breast muscle of the XFBC. The protein-protein interaction network was constructed and eight genes were clustered in the module. We identified nine hub genes, including TYR, TYRP1, DCT, GPR143, MLANA, SLC24A5, GPNMB, MLPH, and EDNRB2. Taken together, the DEGs and hub genes identified in the study provide a solid basis for the study of the genetic regulatory mechanisms involved the melanogenesis in the breast muscle of the XFBC. Key words: Xuefeng black bone chicken, breast muscle, RNA-Seq, melanogenesis, 1. Introduction The black bone chicken is one of the most important poultry genetic resources in China (Li et al. 2020). The productions of black bone chicken are very popular [...]