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

Abstract

&lt;div&gt;Abstract&lt;p&gt;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 &lt;i&gt;COMMD3:BMI1&lt;/i&gt; fusion expression is significantly increased in prostate cancer disease in an order: normal tissue &lt; primary &lt; metastatic tumors (Mets). Although elevated &lt;i&gt;TMPRSS-ERG/ETV&lt;/i&gt; fusion is reported in prostate cancer, we identified a subtype of Mets exhibiting low &lt;i&gt;TMPRSS:ETV&lt;/i&gt; and high &lt;i&gt;COMMD3:BMI1&lt;/i&gt;. We delineated the mechanism and function of COMMD3 and &lt;i&gt;COMMD3:BMI1&lt;/i&gt; 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 &lt;i&gt;COMMD3&lt;/i&gt; 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 &lt;i&gt;COMMD3:BMI1&lt;/i&gt; and COMMD3 regulate &lt;i&gt;C-MYC&lt;/i&gt; transcription and &lt;i&gt;C-MYC&lt;/i&gt; downstream pathway. The ChIP analysis showed that COMMD3 protein is recruited at the promoter of &lt;i&gt;C-MYC&lt;/i&gt; gene. On the basis of these data, we investigated the relevance of &lt;i&gt;COMMD3:BMI1&lt;/i&gt; and COMMD3 as therapeutic targets using &lt;i&gt;in vitro&lt;/i&gt; and xenograft mouse models. We show that siRNA-mediated targeting of &lt;i&gt;COMMD3:BMI1&lt;/i&gt; and &lt;i&gt;COMMD3&lt;/i&gt; significantly decreases (i) &lt;i&gt;C-MYC&lt;/i&gt; expression in BRD/BET inhibitor–resistant cells, (ii) proliferation/invasion &lt;i&gt;in vitro&lt;/i&gt;, and (iii) growth of prostate cancer cell tumors in mice. The IHC analysis of tumors confirmed the targeting of COMMD3-regulated molecular pathway under &lt;i&gt;in vivo&lt;/i&gt; conditions. We conclude that &lt;i&gt;COMMD3:BMI1&lt;/i&gt; and COMMD3 are potential progression biomarkers and therapeutic targets of metastatic prostate cancer.&lt;/p&gt;&lt;/div&gt;