Identification of the epigenetic reader CBX2 as a potential drug target in advanced prostate cancer

Abstract

BackgroundWhile localized prostate cancer (PCa) can be effectively cured, metastatic disease inevitably progresses to a lethal state called castration-resistant prostate cancer (CRPC). Emerging evidence suggests that aberrant epigenetic repression by the polycomb group (PcG) complexes fuels PCa progression, providing novel therapeutic opportunities.ResultsIn the search for potential epigenetic drivers of CRPC, we analyzed the molecular profile of PcG members in patient-derived xenografts and clinical samples. Overall, our results identify the PcG protein and methyl-lysine reader CBX2 as a potential therapeutic target in advanced PCa. We report that CBX2 was recurrently up-regulated in metastatic CRPC and that elevated CBX2 expression was correlated with poor clinical outcome in PCa cohorts. Furthermore, CBX2 depletion abrogated cell viability and induced caspase 3-mediated apoptosis in metastatic PCa cell lines. Mechanistically explaining this phenotype, microarray analysis in CBX2-depleted cells revealed that CBX2 controls the expression of many key regulators of cell proliferation and metastasis.ConclusionsTaken together, this study provides the first evidence that CBX2 inhibition induces cancer cell death, positioning CBX2 as an attractive drug target in lethal CRPC.

CBX2 is a functional target of miRNA let‐7a and acts as a tumor promoter in osteosarcoma

“…In addition, PRC1 promotes cancer cell proliferation through regulating the PcG activity in cancer. Recent study has revealed that CBX2 was significantly upregulated in breast cancer and prostate cancer and may serve as a prognostic biomarker . Consistent with this previous study, our study confirmed the dramatically upregulated CBX2 in osteosarcoma and high CBX2 expression was correlated with metastasis, recurrence, and chemotherapy response, as well as unfavorable prognosis in patients with osteosarcoma.…”

“…In agreement with our results, Clermont et al reported that CBX2 silencing could inhibit cell proliferation and metastasis in prostate cancer. Moreover, CBX2 could regulate the expression of key genes involved in cancer proliferation and metastasis . These results are consistent with weaken proliferative features of CBX2‐deficient animals .…”

“…The chromobox (CBX2) family, a component of PRC1, is comprised of CBX2/4/6/7/8 . Recent studies have revealed that CBX2 is overexpressed in several cancer type and plays a critical role in tumorigenesis and progression . However, the expression pattern and functional role of CBX2 in osteosarcoma and its regulatory mechanisms are still unknown.…”

Elevated expression of a pharmacologic Polycomb signature predicts poor prognosis in gastric and breast cancer

“…In accordance with numerous other articles, we have previously demonstrated that silencing of PcG targets can predict poor prognosis in some aggressive tumor types [5,20]. Here, we report the opposite in gastric and breast cancer, wherein an upregulation of DZNeP target genes is observed in more aggressive tumors.…”

“…This paradigm shift has generated considerable interest in exploring the cancer epigenome in the search for clinical tools to diagnose, classify, and treat human tumors [4]. Notably, extensive evidence has demonstrated that a group of epigenetic regulators called the Polycomb Group (PcG) proteins play critical roles in human cancer and may be exploited clinically [5,6]. PcG proteins assemble in two main Polycomb Repressive Complexes (PRC1 and PRC2) known to silence key tumor suppressor genes, thereby contributing to tumorigenesis and metastasic dissemination [7].…”