The ubiquitin ligase Siah2 regulates tumorigenesis and metastasis by HIF-dependent and -independent pathways

Jianfei Qi, Koh Nakayama, Supriya Gaitonde, James S. Goydos, Stan Krajewski, Alexey Eroshkin, Dafna Bar-Sagi, David Bowtell, Ze'ev Ronai

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75 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)16713-16718
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number43
DOIs
StatePublished - Oct 28 2008

All Science Journal Classification (ASJC) codes

  • General

Keywords

  • HIF
  • Hypoxia
  • Prolyl hydroxylase
  • Siah
  • Sprouty

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    Qi, J., Nakayama, K., Gaitonde, S., Goydos, J. S., Krajewski, S., Eroshkin, A., Bar-Sagi, D., Bowtell, D., & Ronai, Z. (2008). The ubiquitin ligase Siah2 regulates tumorigenesis and metastasis by HIF-dependent and -independent pathways. Proceedings of the National Academy of Sciences of the United States of America, 105(43), 16713-16718. https://doi.org/10.1073/pnas.0804063105