Our work on the ubiquitin ligase Siah2 has revealed its important role in the most aggressive forms of prostate cancer (PCa)—castration resistant PCa (CRPC) and neuroendocrine PCa (NEPC). In both cases, inhibition of Siah2 had a remarkable effect on the inhibition of both forms of prostate cancer, suggesting that inhibition of Siah2 could be a new line of therapy.
Understanding the mechanism underlying the regulation of the Androgen Receptor (AR), which is a central player in the development of CRPC, holds promise for overcoming the challenge of treating CRPC. We found that the ubiquitin ligase Siah2 targets a select pool of NCOR1-bound, transcriptionally inactive AR for ubiquitin-dependent degradation, thereby promoting expression of select AR target genes implicated in lipid metabolism, cell motility and proliferation. Siah2 is required for prostate cancer cell growth under androgen deprivation in vitro and in vivo, and Siah2 inhibition promotes prostate cancer regression upon castration. Notably, Siah2 expression is markedly increased in human CRPCs. Inhibition of Siah2 may therefore hold promise for treatment or prevention of CRPC.
Neuroendocrine phenotype (NE) is seen in >30% of prostate adenocarcinoma, and NE tumors are implicated in aggressive prostate cancer. Formation of NE prostate tumors in the TRAMP mouse model was suppressed in mice lacking the ubiquitin ligase Siah2, in part through its regulation of HIF1alpha availability. We found that HIF1alpha, when available, formed a heterodimeric complex with FOXOA2, a transcription factor that is expressed in NE tissues. This cooperation is enhanced by p399, which is recruited to this complex and results in the activation of select HIF1alpha regulated genes. Among the more critical mapped as part of this regulatory cue are Sox9, Hes6 and Jmjd1a. These HIF-regulated genes are highly expressed in metastatic PCa and are required for hypoxia mediated NE phenotype, metastasis in PCa and the formation of NE tumors. Tissue specific expression of FoxA2 combined with Siah2-dependent HIF1alpha availability enables this transcriptional program, which is sufficient to drive NE tumor and NE phenotype in PCa. Targeting Siah2 is therefore expected to reduce HIF1alpha availability and its ability to heterodimerize with FoxA2, thereby inhibiting the formation of NE tumors and lesions.