Growing evidence indicates that ubiquitin ligases play a critical role in the hypoxia response. Among them, Siah2, a RING finger ligase, is an important regulator of pathways activated under hypoxia. Siah2 regulates prolyl hydroxylases PHD3 and 1 under oxygen concentration of 2% to 5%, thereby allowing accumulation of hypoxia-inducible factor (HIF)-1α, a master regulator of the hypoxia response within the range of physiological normoxic to mild hypoxic conditions. Growing evidence also indicates an important function for Siah2 in tumor development and progression based on pancreatic cancer, mammary tumor, and melanoma mouse models. This review summarizes our current understanding of Siah2 regulation and function with emphasis on hypoxia and tumorigenesis. (Mol Cancer Res 2009;7(4):443–51)

Significance: Formation of androgen receptor splicing variant 7 (AR-V7), a constitutively active form of AR, plays a key role in the resistance of prostate cancer to hormone therapy. However, the mechanisms that regulate AR-V7 generation are poorly understood. Here, we identified a new role for histone demethylase JMJD1A (Jumonji domain containing 1A) in the formation of AR-V7 in prostate cancer cells. We found that JMJD1A facilitated recruitment of a splicing factor, heterogeneous nuclear ribonucleoprotein F, for alternative splicing and generation of AR-V7. The findings suggest that targeting JMJD1A may provide new therapeutic opportunity for prostate cancer.

The ubiquitin ligase Siah2 has been shown to regulate prolyl hydroxylase 3 (PHD3) stability with concomitant effect on HIF-1α availability. Because HIF-1α is implicated in tumorigenesis and metastasis, we used SW1 mouse melanoma cells, which develop primary tumors with a propensity to metastasize, in a syngeneic mouse model to assess a possible role for Siah2 in these processes. Inhibiting Siah2 activity by expressing a peptide designed to outcompete association of Siah2-interacting proteins reduced metastasis through HIF-1α without affecting tumorigenesis. Conversely, inhibiting Siah2 activity by means of a dominant-negative Siah2 RING mutant primarily reduced tumorigenesis through the action of Sprouty 2, a negative regulator of Ras signaling. Consistent with our findings, reduced expression of PHD3 and Sprouty2 was observed in more advanced stages of melanoma tumors. Using complementary approaches, our data establish the role of Siah2 in tumorigenesis and metastasis by HIF-dependent and -independent mechanisms.