<i>COMMD3:BMI1</i> Fusion and COMMD3 Protein Regulate <i>C-MYC</i> Transcription: Novel Therapeutic Target for Metastatic Prostate Cancer

Abstract

Gene rearrangement is reported to be associated to the aggressive phenotype and poor prognosis in prostate cancer. We identified a gene fusion between a transcription repressor (BMI1) and transcriptional factor (COMMD3) in human prostate cancer. We show that <i>COMMD3:BMI1</i> fusion expression is significantly increased in prostate cancer disease in an order: normal tissue < primary < metastatic tumors (Mets). Although elevated <i>TMPRSS-ERG/ETV</i> fusion is reported in prostate cancer, we identified a subtype of Mets exhibiting low <i>TMPRSS:ETV</i> and high <i>COMMD3:BMI1</i> We delineated the mechanism and function of COMMD3 and <i>COMMD3:BMI1</i> in prostate cancer. We show that COMMD3 level is elevated in prostate cancer cell models, PDX models (adenocarcinoma, NECaP), and Mets. The analysis of TCGA/NIH/GEO clinical data showed a positive correlation between increased <i>COMMD3</i> expression to the disease recurrence and poor survival in prostate cancer. We show that COMMD3 drives proliferation of normal cells and promotes migration/invasiveness of neoplastic cells. We show that <i>COMMD3:BMI1</i> and COMMD3 regulate <i>C-MYC</i> transcription and <i>C-MYC</i> downstream pathway. The ChIP analysis showed that COMMD3 protein is recruited at the promoter of <i>C-MYC</i> gene. On the basis of these data, we investigated the relevance of <i>COMMD3:BMI1</i> and COMMD3 as therapeutic targets using <i>in vitro</i> and xenograft mouse models. We show that siRNA-mediated targeting of <i>COMMD3:BMI1</i> and <i>COMMD3</i> significantly decreases (i) <i>C-MYC</i> expression in BRD/BET inhibitor-resistant cells, (ii) proliferation/invasion <i>in vitro</i>, and (iii) growth of prostate cancer cell tumors in mice. The IHC analysis of tumors confirmed the targeting of COMMD3-regulated molecular pathway under <i>in vivo</i> conditions. We conclude that <i>COMMD3:BMI1</i> and COMMD3 are potential progression biomarkers and therapeutic targets of metastatic prostate cancer.