Gain-of-function mutant p53 activates small GTPase Rac1 through SUMOylation to promote tumor progression

Xuetian Yue; Cen Zhang; Yuhan Zhao; Juan Liu; Alan W. Lin; Victor M. Tan; Justin M. Drake; Lianxin Liu; Michael N. Boateng; Jun Li; Zhaohui Feng; Wenwei Hu

doi:10.1101/gad.301564.117

Gain-of-function mutant p53 activates small GTPase Rac1 through SUMOylation to promote tumor progression

Xuetian Yue, Cen Zhang, Yuhan Zhao, Juan Liu, Alan W. Lin, Victor M. Tan, Justin M. Drake, Lianxin Liu, Michael N. Boateng, Jun Li, Zhaohui Feng, Wenwei Hu

Research output: Contribution to journal › Article › peer-review

43 Scopus citations

Abstract

Tumor suppressor p53 is frequently mutated in human cancer. Mutant p53 often promotes tumor progression through gain-of-function (GOF) mechanisms. However, the mechanisms underlying mutant p53 GOF are not well understood. In this study, we found that mutant p53 activates small GTPase Rac1 as a critical mechanism for mutant p53 GOF to promote tumor progression. Mechanistically, mutant p53 interacts with Rac1 and inhibits its interaction with SUMO-specific protease 1 (SENP1), which in turn inhibits SENP1-mediated de-SUMOylation of Rac1 to activate Rac1. Targeting Rac1 signaling by RNAi, expression of the dominant-negative Rac1 (Rac1 DN), or the specific Rac1 inhibitor NSC23766 greatly inhibits mutant p53 GOF in promoting tumor growth and metastasis. Furthermore, mutant p53 expression is associated with enhanced Rac1 activity in clinical tumor samples. These results uncover a new mechanism for Rac1 activation in tumors and, most importantly, reveal that activation of Rac1 is an unidentified and critical mechanism for mutant p53 GOF in tumorigenesis, which could be targeted for therapy in tumors containing mutant p53.

Original language	English (US)
Pages (from-to)	1641-1654
Number of pages	14
Journal	Genes and Development
Volume	31
Issue number	16
DOIs	https://doi.org/10.1101/gad.301564.117
State	Published - Aug 15 2017
Externally published	Yes

Bibliographical note

Funding Information:
This study was supported by National Institutes of Health (NIH) grants 1R01CA160558-01 and 1R01CA203965 and Department

Funding Information:
of Defense grant W81XWH-16-1-0358 to W.H.; and NIH grant R01CA143204, the New Jersey Health Foundation, and Bush Medical Research Award to Z.F. X.Y. is supported by a New Jersey Commission on Cancer Research Post-doctoral Fellowship Award. Y.Z. is supported by NIH grant F99CA222734. W.H. and Z.F. designed experiments, analyzed the data, and wrote manuscript; X.Y., C.Z., Y.Z., J. Liu, A.W.L., M.N.B., and J. Li carried out the experiments and analyzed the data; and V.M.T., J.M.D., and L.L. carried out cancer sample data analysis.

Publisher Copyright:
© 2017 Yue et al.

Keywords

Gain of function
Metastasis
Mutant p53
Rac1
Sumoylation
Tumorigenesis

UN SDGs

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

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10.1101/gad.301564.117

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5647935

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@article{ce50379117104431a1711e26aba2ec75,

title = "Gain-of-function mutant p53 activates small GTPase Rac1 through SUMOylation to promote tumor progression",

abstract = "Tumor suppressor p53 is frequently mutated in human cancer. Mutant p53 often promotes tumor progression through gain-of-function (GOF) mechanisms. However, the mechanisms underlying mutant p53 GOF are not well understood. In this study, we found that mutant p53 activates small GTPase Rac1 as a critical mechanism for mutant p53 GOF to promote tumor progression. Mechanistically, mutant p53 interacts with Rac1 and inhibits its interaction with SUMO-specific protease 1 (SENP1), which in turn inhibits SENP1-mediated de-SUMOylation of Rac1 to activate Rac1. Targeting Rac1 signaling by RNAi, expression of the dominant-negative Rac1 (Rac1 DN), or the specific Rac1 inhibitor NSC23766 greatly inhibits mutant p53 GOF in promoting tumor growth and metastasis. Furthermore, mutant p53 expression is associated with enhanced Rac1 activity in clinical tumor samples. These results uncover a new mechanism for Rac1 activation in tumors and, most importantly, reveal that activation of Rac1 is an unidentified and critical mechanism for mutant p53 GOF in tumorigenesis, which could be targeted for therapy in tumors containing mutant p53.",

keywords = "Gain of function, Metastasis, Mutant p53, Rac1, Sumoylation, Tumorigenesis",

author = "Xuetian Yue and Cen Zhang and Yuhan Zhao and Juan Liu and Lin, {Alan W.} and Tan, {Victor M.} and Drake, {Justin M.} and Lianxin Liu and Boateng, {Michael N.} and Jun Li and Zhaohui Feng and Wenwei Hu",

note = "Funding Information: This study was supported by National Institutes of Health (NIH) grants 1R01CA160558-01 and 1R01CA203965 and Department Funding Information: of Defense grant W81XWH-16-1-0358 to W.H.; and NIH grant R01CA143204, the New Jersey Health Foundation, and Bush Medical Research Award to Z.F. X.Y. is supported by a New Jersey Commission on Cancer Research Post-doctoral Fellowship Award. Y.Z. is supported by NIH grant F99CA222734. W.H. and Z.F. designed experiments, analyzed the data, and wrote manuscript; X.Y., C.Z., Y.Z., J. Liu, A.W.L., M.N.B., and J. Li carried out the experiments and analyzed the data; and V.M.T., J.M.D., and L.L. carried out cancer sample data analysis. Publisher Copyright: {\textcopyright} 2017 Yue et al.",

year = "2017",

month = aug,

day = "15",

doi = "10.1101/gad.301564.117",

language = "English (US)",

volume = "31",

pages = "1641--1654",

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T1 - Gain-of-function mutant p53 activates small GTPase Rac1 through SUMOylation to promote tumor progression

AU - Yue, Xuetian

AU - Zhang, Cen

AU - Zhao, Yuhan

AU - Liu, Juan

AU - Lin, Alan W.

AU - Tan, Victor M.

AU - Drake, Justin M.

AU - Liu, Lianxin

AU - Boateng, Michael N.

AU - Li, Jun

AU - Feng, Zhaohui

AU - Hu, Wenwei

N1 - Funding Information: This study was supported by National Institutes of Health (NIH) grants 1R01CA160558-01 and 1R01CA203965 and Department Funding Information: of Defense grant W81XWH-16-1-0358 to W.H.; and NIH grant R01CA143204, the New Jersey Health Foundation, and Bush Medical Research Award to Z.F. X.Y. is supported by a New Jersey Commission on Cancer Research Post-doctoral Fellowship Award. Y.Z. is supported by NIH grant F99CA222734. W.H. and Z.F. designed experiments, analyzed the data, and wrote manuscript; X.Y., C.Z., Y.Z., J. Liu, A.W.L., M.N.B., and J. Li carried out the experiments and analyzed the data; and V.M.T., J.M.D., and L.L. carried out cancer sample data analysis. Publisher Copyright: © 2017 Yue et al.

PY - 2017/8/15

Y1 - 2017/8/15

N2 - Tumor suppressor p53 is frequently mutated in human cancer. Mutant p53 often promotes tumor progression through gain-of-function (GOF) mechanisms. However, the mechanisms underlying mutant p53 GOF are not well understood. In this study, we found that mutant p53 activates small GTPase Rac1 as a critical mechanism for mutant p53 GOF to promote tumor progression. Mechanistically, mutant p53 interacts with Rac1 and inhibits its interaction with SUMO-specific protease 1 (SENP1), which in turn inhibits SENP1-mediated de-SUMOylation of Rac1 to activate Rac1. Targeting Rac1 signaling by RNAi, expression of the dominant-negative Rac1 (Rac1 DN), or the specific Rac1 inhibitor NSC23766 greatly inhibits mutant p53 GOF in promoting tumor growth and metastasis. Furthermore, mutant p53 expression is associated with enhanced Rac1 activity in clinical tumor samples. These results uncover a new mechanism for Rac1 activation in tumors and, most importantly, reveal that activation of Rac1 is an unidentified and critical mechanism for mutant p53 GOF in tumorigenesis, which could be targeted for therapy in tumors containing mutant p53.

AB - Tumor suppressor p53 is frequently mutated in human cancer. Mutant p53 often promotes tumor progression through gain-of-function (GOF) mechanisms. However, the mechanisms underlying mutant p53 GOF are not well understood. In this study, we found that mutant p53 activates small GTPase Rac1 as a critical mechanism for mutant p53 GOF to promote tumor progression. Mechanistically, mutant p53 interacts with Rac1 and inhibits its interaction with SUMO-specific protease 1 (SENP1), which in turn inhibits SENP1-mediated de-SUMOylation of Rac1 to activate Rac1. Targeting Rac1 signaling by RNAi, expression of the dominant-negative Rac1 (Rac1 DN), or the specific Rac1 inhibitor NSC23766 greatly inhibits mutant p53 GOF in promoting tumor growth and metastasis. Furthermore, mutant p53 expression is associated with enhanced Rac1 activity in clinical tumor samples. These results uncover a new mechanism for Rac1 activation in tumors and, most importantly, reveal that activation of Rac1 is an unidentified and critical mechanism for mutant p53 GOF in tumorigenesis, which could be targeted for therapy in tumors containing mutant p53.

KW - Gain of function

KW - Metastasis

KW - Mutant p53

KW - Rac1

KW - Sumoylation

KW - Tumorigenesis

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ER -

Gain-of-function mutant p53 activates small GTPase Rac1 through SUMOylation to promote tumor progression

Abstract

Bibliographical note

Keywords

UN SDGs

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