Ubiquitin-conjugating enzyme Ubc13 controls breast cancer metastasis through a TAK1-p38 MAP kinase cascade

Xuefeng Wu, Weizhou Zhang, Joan Font-Burgada, Trenis Palmer, Alexander S. Hamil, Subhra K. Biswas, Michael Poidinger, Nicholas Borcherding, Qing Xie, Lesley G. Ellies, Nikki K. Lytle, Li Wha Wu, Raymond G. Fox, Jing Yang, Steven F. Dowdy, Tannishtha Reya, Michael Karin

Research output: Contribution to journalArticlepeer-review

56 Citations (Scopus)

Abstract

Metastatic spread is the leading cause of cancer mortality. Breast cancer (BCa) metastatic recurrence can happen years after removal of the primary tumor. Here we show that Ubc13, an E2 enzyme that catalyzes K63-linked protein polyubiquitination, is largely dispensable for primary mammary tumor growth but is required for metastatic spread and lung colonization by BCa cells. Loss of Ubc13 inhibited BCa growth and survival only at metastatic sites. Ubc13 was dispensable for transforming growth factor β (TGFβ)-induced SMAD activation but was required for activation of non-SMAD signaling via TGFâ-activating kinase 1 (TAK1) and p38, whose activity controls expression of numerous metastasis promoting genes. p38 activation restored metastatic activity to Ubc13-deficient cells, and its pharmacological inhibition attenuated BCa metastasis in mice, suggesting it is a therapeutic option for metastatic BCa.

Original languageEnglish
Pages (from-to)13870-13875
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number38
DOIs
Publication statusPublished - 2014 Sep 23

All Science Journal Classification (ASJC) codes

  • General

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