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

doi:10.1073/pnas.1414358111

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 journal › Article › peer-review

90 Scopus citations

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 language	English
Pages (from-to)	13870-13875
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	111
Issue number	38
DOIs	https://doi.org/10.1073/pnas.1414358111
State	Published - Sep 23 2014

Keywords

Animals
Breast Neoplasms/enzymology
Cell Line, Tumor
Female
Heterografts
Humans
MAP Kinase Kinase Kinases/genetics
MAP Kinase Signaling System
Mice
Mice, Inbred NOD
Mice, SCID
Neoplasm Metastasis
Neoplasm Proteins/genetics
Neoplasm Transplantation
Ubiquitin-Conjugating Enzymes/genetics
p38 Mitogen-Activated Protein Kinases/genetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1073/pnas.1414358111

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Wu, X., Zhang, W., Font-Burgada, J., Palmer, T., Hamil, A. S., Biswas, S. K., Poidinger, M., Borcherding, N., Xie, Q., Ellies, L. G., Lytle, N. K., Wu, L. W., Fox, R. G., Yang, J., Dowdy, S. F., Reya, T., & Karin, M. (2014). Ubiquitin-conjugating enzyme Ubc13 controls breast cancer metastasis through a TAK1-p38 MAP kinase cascade. Proceedings of the National Academy of Sciences of the United States of America, 111(38), 13870-13875. https://doi.org/10.1073/pnas.1414358111

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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 TGF{\^a}-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.",

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

year = "2014",

month = sep,

day = "23",

doi = "10.1073/pnas.1414358111",

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journal = "Proceedings of the National Academy of Sciences of the United States of America",

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Wu, X, Zhang, W, Font-Burgada, J, Palmer, T, Hamil, AS, Biswas, SK, Poidinger, M, Borcherding, N, Xie, Q, Ellies, LG, Lytle, NK, Wu, LW, Fox, RG, Yang, J, Dowdy, SF, Reya, T & Karin, M 2014, 'Ubiquitin-conjugating enzyme Ubc13 controls breast cancer metastasis through a TAK1-p38 MAP kinase cascade', Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 38, pp. 13870-13875. https://doi.org/10.1073/pnas.1414358111

TY - JOUR

T1 - Ubiquitin-conjugating enzyme Ubc13 controls breast cancer metastasis through a TAK1-p38 MAP kinase cascade

AU - Wu, Xuefeng

AU - Zhang, Weizhou

AU - Font-Burgada, Joan

AU - Palmer, Trenis

AU - Hamil, Alexander S.

AU - Biswas, Subhra K.

AU - Poidinger, Michael

AU - Borcherding, Nicholas

AU - Xie, Qing

AU - Ellies, Lesley G.

AU - Lytle, Nikki K.

AU - Wu, Li Wha

AU - Fox, Raymond G.

AU - Yang, Jing

AU - Dowdy, Steven F.

AU - Reya, Tannishtha

AU - Karin, Michael

PY - 2014/9/23

Y1 - 2014/9/23

N2 - 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.

AB - 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.

KW - Animals

KW - Breast Neoplasms/enzymology

KW - Cell Line, Tumor

KW - Female

KW - Heterografts

KW - Humans

KW - MAP Kinase Kinase Kinases/genetics

KW - MAP Kinase Signaling System

KW - Mice

KW - Mice, Inbred NOD

KW - Mice, SCID

KW - Neoplasm Metastasis

KW - Neoplasm Proteins/genetics

KW - Neoplasm Transplantation

KW - Ubiquitin-Conjugating Enzymes/genetics

KW - p38 Mitogen-Activated Protein Kinases/genetics

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U2 - 10.1073/pnas.1414358111

DO - 10.1073/pnas.1414358111

M3 - Article

C2 - 25189770

SN - 0027-8424

VL - 111

SP - 13870

EP - 13875

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 38

ER -

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

Abstract

Keywords

UN SDGs

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