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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.

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.

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.

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.