The E3 Ubiquitin Ligase Siah2 Contributes to Castration-Resistant Prostate Cancer by Regulation of Androgen Receptor Transcriptional Activity

Abstract

SUMMARY Understanding the mechanism underlying the regulation of the androgen receptor (AR), a central player in the development of castration-resistant prostate cancer (CRPC), holds promise for overcoming the challenge of treating CRPC. We demonstrate 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 conditions in vitro and in vivo, and Siah2 inhibition promotes prostate cancer regression upon castration. Notably, Siah2 expression is markedly increased in human CRPCs. Collectively, we find that selective regulation of AR transcriptional activity by the ubiquitin ligase Siah2 is important for CRPC development.

The inducible E3 ubiquitin ligases SIAH1 and SIAH2 perform critical roles in breast and prostate cancers

“…Of note, nuclear SIAH2 was detected in 144 tumors and was linked to a shorter time to BF, which was seen in 22 patients in a 2.3 year follow-up analysis [87]. Furthermore, SIAH2 regulates the PSA gene under low and physiologic concentrations of androgens [41] and this could be linked to prostate cancer recurrence. These data rather suggest tumorpromoting functions of SIAH2 in this type of cancer.…”

“…Future experiments are anticipated on this interesting crosstalk. Immunohistochemistry of human prostate cancer specimens (n = 194) showed that mostly nuclear SIAH2 signals became decreased upon androgen deprivation therapy/prostatectomy (Table 1) and that SIAH2 levels increased upon disease recurrence [41]. These findings demonstrate that besides its regulation by female sex hormones (Table 1), SIAH2 is somehow controlled by male sex hormones.…”

“…For example, acquired resistance against the ER antagonist 4-hydroxytamoxifen has been linked to EGFR signaling and can be blocked with the EGFR inhibitor gefitinib [40]. In addition, SIAH2 mRNA levels were predictive for recurrent disease and progression/metastasis-free [49,95] androgen deprivation/ prostatectomy prostate cancer cells SIAH2 [41] proteasomal inhibition various cell types SIAH1 and SIAH2; inhibition of self-degradation [5] WNT-5a human epithelial kidney and colon carcinoma cells SIAH2…”

Androgen receptor signaling in castration-resistant prostate cancer: a lesson in persistence

“…In addition to SPOP, several other E3 ligases including Siah2 (Qi et al 2013), RNF6 (Xu et al 2009b), MDM2 (Lin et al 2002) and CHIP (Sarkar et al 2014) have been shown to mediate AR ubiquitylation, and these factors collectively enable another level of complexity in terms of AR regulation. Elucidating mechanisms underlying AR degradation has facilitated the rational design of proteolysis-targeting chimeras (PROTACs), which link an AR-binding element to a degron tag, such as an E3 ligaserecruiting moiety (Tang et al 2009) or a hydrophobic tag (Gustafson et al 2015), resulting in targeting of the AR to the UPS for degradation.…”

Ubiquitin-Proteasome Pathway and Prostate Cancer

“…Conversely, knock-down of PMEPA1 leads to elevated levels of AR protein, and AR transcriptional targets like prostate-specific antigen (PSA) [21]. Among others, the E3 ubiquitin ligase Siah2 contributes to prostate cancer cell proliferation and also makes cells castration-resistant by selective regulation of AR transcriptional activity [23]. Usually, Siah2 targets transcriptionally inactive AR for degradation.…”