MED12 overexpression is a frequent event in castration-resistant prostate cancer

Abstract

In a recent effort to unravel the molecular basis of prostate cancer (PCa), Barbieri and colleagues using whole-exome sequencing identified a novel recurrently mutated gene, MED12, in 5.4% of primary PCa. MED12, encoding a subunit of the Mediator complex, is a transducer of Wnt/b-catenin signaling, linked to modulation of hedgehog signaling and to the regulation of transforming growth factor beta (TGFb)-receptor signaling. Therefore, these studies prompted us to investigate the relevance of MED12 in PCa. Expression of MED12, SMAD3 phosphorylation, and proliferation markers was assessed by immunohistochemistry on tissue microarrays from 633 patients. siRNA-mediated knockdown of MED12 was carried out on PCa cell lines followed by cellular proliferation assays, cell cycle analysis, apoptosis assays, and treatments with recombinant TGFb3. We found nuclear overexpression of MED12 in 40% (28/70) of distant metastatic castration-resistant prostate cancer (CRPC MET ) and 21% (19/90) of local-recurrent CRPC (CRPC LOC ) in comparison with frequencies of less than 11% in androgen-sensitive PCa, and no overexpression in benign prostatic tissues. MED12 expression was significantly correlated with high proliferative activity in PCa tissues, whereas knockdown of MED12 decreased proliferation, reduced G1-to S-phase transition, and increased the expression of the cell cycle inhibitor p27. TGFb signaling activation associates with MED12 nuclear overexpression in tissues and results in a strong increase in MED12 nuclear expression in cell lines. Furthermore, MED12 knockdown

Germline BRCA2 mutations drive prostate cancers with distinct evolutionary trajectories

“…The MED12L / MED12 axis is implicated in metastatic sporadic PCa, with MED12 nuclear overexpression common in mCRPC and localized recurrent PCa but not in localized primary PCa or benign prostate tissue26. MED12 SNVs, which occur in both localized and advanced PCa, are also implicated in prostate tumourigenesis27 and genome instability2829.…”

Expression of CDK8 and CDK8-interacting Genes as Potential Biomarkers in Breast Cancer

“…On the other hand, MED12, in contrast to CDK8, is found not only in the nucleus but also in the cytoplasm, where MED12 was shown to interact with TGFβR2 and to inhibit the TGFβ pathway, an activity independent of the role of the nuclear MED12 in the transcriptional Mediator complex [37]. Furthermore, while MED12 displays tumor-promoting activities in prostate cancer [38], it undergoes loss-of-function mutations in uterine leiomyomas [39]. Remarkably, the same MED12 mutations were also found and characterized in breast fibroadenomas [40] and benign phyllodes tumors of the breast [41, 42] but in the case of the fibroadenomas these mutations (which are different from those found in the TCGA breast cancer panel) occurred not in the epithelial mammary cells but rather in the stromal tissue, where they were associated with dysregulated estrogen signaling and extracellular matrix organization [40].…”

Pan-Cancer Analysis of the Mediator Complex Transcriptome Identifies CDK19 and CDK8 as Therapeutic Targets in Advanced Prostate Cancer

“…Most evidence has been gathered for the kinase module subunit CDK8, which has been linked to colon and pancreatic cancer (8,9) and was also investigated as a potential target in cancer therapy (10,11). Other subunits have also been reported in neoplastic conditions such as MED12 in uterine leiomyomas, fibroepithelial breast tumors, and prostate cancer (12)(13)(14), MED15 in prostate cancer and head and neck cancer (15,16), and cyclin C in acute lymphoblastic leukemia (17). In addition, some subunits have been linked to altered hormone receptor signaling such as MED1 in breast cancer and prostate cancer (18,19).…”