Abstract
Epigenetic alterations that lead to dysregulated gene expression in the progression of castration-resistant prostate cancer (CRPC) remain elusive. Here, we investigated the role of histone deubiquitinase MYSM1 in the pathogenesis of prostate cancer (PCa). Tissues and public datasets of PCa were evaluated for MYSM1 levels. We explored the effects of MYSM1 on cell proliferation, senescence and viability both in vitro and in vivo. Integrative database analyses and co-immunoprecipitation assays were performed to elucidate genomic association of MYSM1 and MYSM1-involved biological interaction network in PCa. We observed that MYSM1 were downregulated in CRPC compared to localized prostate tumors. Knockdown of MYSM1 promoted cell proliferation and suppressed senescence of CRPC cells under condition of androgen ablation. MYSM1 downregulation enhanced the tumorigenic ability in nude mice. Integrative bioinformatic analyses of the significantly associated genes with MYSM1 revealed MYSM1-correlated pathways, providing substantial clues as to the role of MYSM1 in PCa. MYSM1 was able to bind to androgen receptor instead of increasing its expression and knockdown of MYSM1 resulted in activation of Akt/c-Raf/GSK-3β signaling. Together, our findings indicate that MYSM1 is pivotal in CRPC pathogenesis and may be established as a potential target for future treatment.
Highlights
Prostate cancer (PCa) is one leading cause of cancerrelated death among men in Western countries [1]
We found that compared with localized PCa patients, the expression of Myb-like SWIRM and MPN domains 1 (MYSM1) was significantly downregulated in metastatic castration-resistant prostate cancer (CRPC) patients (Figure 1E)
We found that MYSM1 levels are downregulated in CRPC tissues compared to localized primary tumor tissues, indicating a potential role for MYSM1 in the switch to castration resistance
Summary
Prostate cancer (PCa) is one leading cause of cancerrelated death among men in Western countries [1]. The heterogeneity in AR expression or activity suggest that AR deficiency may be proposed as a potential way in which prostate cancer cells escape androgen deprivation therapy [7], with compensatory signaling pathways activated concomitantly. The PI3K/Akt pathway, which is antagonized by tumor suppressor PTEN, is constitutively activated in prostate cancers with PTEN deficiency, leading to enhanced tumor cell survival, metastasis and castration-resistant growth [12, 18, 19]. Combination therapy cotargeting PI3K/Akt and AR signaling leads to significant regression of prostate cancer when compared with monotherapies [23,24,25], suggesting a coordinative role in supporting tumor survival
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