The deubiquitination enzyme USP46 functions as a tumor suppressor by controlling PHLPP-dependent attenuation of Akt signaling in colon cancer

X. Li; P. D. Stevens; H. Yang; P. Gulhati; W. Wang; B. M. Evers; T. Gao

doi:10.1038/onc.2012.66

The deubiquitination enzyme USP46 functions as a tumor suppressor by controlling PHLPP-dependent attenuation of Akt signaling in colon cancer

X. Li, P. D. Stevens, H. Yang, P. Gulhati, W. Wang, B. M. Evers, T. Gao

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

90 Scopus citations

Abstract

PH domain leucine-rich-repeats protein phosphatase (PHLPP) is a family of Ser/Thr protein phosphatases that serve as tumor suppressors by negatively regulating Akt. Our recent studies have demonstrated that the ubiquitin proteasome pathway has an important role in the downregulation of PHLPP in colorectal cancer. In this study, we show that the deubiquitinase USP46 stabilizes the expression of both PHLPP isoforms by reducing the rate of PHLPP degradation. USP46 binds to PHLPP and directly removes the polyubiquitin chains from PHLPP in vitro and in cells. Increased USP46 expression correlates with decreased ubiquitination and upregulation of PHLPP proteins in colon cancer cells, whereas knockdown of USP46 has the opposite effect. Functionally, USP46-mediated stabilization of PHLPP and the subsequent inhibition of Akt result in a decrease in cell proliferation and tumorigenesis of colon cancer cells in vivo. Moreover, reduced USP46 protein level is found associated with poor PHLPP expression in colorectal cancer patient specimens. Taken together, these results indentify a tumor suppressor role of USP46 in promoting PHLPP expression and inhibiting Akt signaling in colon cancer.

Original language	English
Pages (from-to)	471-478
Number of pages	8
Journal	Oncogene
Volume	32
Issue number	4
DOIs	https://doi.org/10.1038/onc.2012.66
State	Published - Jan 24 2013

Bibliographical note

Funding Information:
We thank Dr Wade Harper (Harvard Medical School) for providing USP46, USP7 and USP16 expression plasmids, and Dr Hui-Kuan Lin (University of Texas MD Anderson Cancer Center) for providing His-tagged ubiquitin construct. The Biostatistic Core at the Markey Cancer Center (University of Kentucky) provided assistant with the statistical analysis in our study. This work was supported by NIH R01CA133429 (TG), American Cancer Society RSG0822001TBE (TG), P20CA1530343 (UK GI SPORE) and R01DK48498 (BME).

Funding

We thank Dr Wade Harper (Harvard Medical School) for providing USP46, USP7 and USP16 expression plasmids, and Dr Hui-Kuan Lin (University of Texas MD Anderson Cancer Center) for providing His-tagged ubiquitin construct. The Biostatistic Core at the Markey Cancer Center (University of Kentucky) provided assistant with the statistical analysis in our study. This work was supported by NIH R01CA133429 (TG), American Cancer Society RSG0822001TBE (TG), P20CA1530343 (UK GI SPORE) and R01DK48498 (BME).

Funders	Funder number
American Cancer Society RSG0822001TBE	P20CA1530343, R01DK48498
National Institutes of Health (NIH)	R01CA133429
National Institute of Diabetes and Digestive and Kidney Diseases	R01DK048498

Keywords

Akt
PHLPP
USP46
deubiquitination
tumor suppressor

ASJC Scopus subject areas

Molecular Biology
Genetics
Cancer Research

UN SDGs

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

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10.1038/onc.2012.66

Cite this

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title = "The deubiquitination enzyme USP46 functions as a tumor suppressor by controlling PHLPP-dependent attenuation of Akt signaling in colon cancer",

abstract = "PH domain leucine-rich-repeats protein phosphatase (PHLPP) is a family of Ser/Thr protein phosphatases that serve as tumor suppressors by negatively regulating Akt. Our recent studies have demonstrated that the ubiquitin proteasome pathway has an important role in the downregulation of PHLPP in colorectal cancer. In this study, we show that the deubiquitinase USP46 stabilizes the expression of both PHLPP isoforms by reducing the rate of PHLPP degradation. USP46 binds to PHLPP and directly removes the polyubiquitin chains from PHLPP in vitro and in cells. Increased USP46 expression correlates with decreased ubiquitination and upregulation of PHLPP proteins in colon cancer cells, whereas knockdown of USP46 has the opposite effect. Functionally, USP46-mediated stabilization of PHLPP and the subsequent inhibition of Akt result in a decrease in cell proliferation and tumorigenesis of colon cancer cells in vivo. Moreover, reduced USP46 protein level is found associated with poor PHLPP expression in colorectal cancer patient specimens. Taken together, these results indentify a tumor suppressor role of USP46 in promoting PHLPP expression and inhibiting Akt signaling in colon cancer.",

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author = "X. Li and Stevens, {P. D.} and H. Yang and P. Gulhati and W. Wang and Evers, {B. M.} and T. Gao",

note = "Funding Information: We thank Dr Wade Harper (Harvard Medical School) for providing USP46, USP7 and USP16 expression plasmids, and Dr Hui-Kuan Lin (University of Texas MD Anderson Cancer Center) for providing His-tagged ubiquitin construct. The Biostatistic Core at the Markey Cancer Center (University of Kentucky) provided assistant with the statistical analysis in our study. This work was supported by NIH R01CA133429 (TG), American Cancer Society RSG0822001TBE (TG), P20CA1530343 (UK GI SPORE) and R01DK48498 (BME).",

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AU - Wang, W.

AU - Evers, B. M.

AU - Gao, T.

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The deubiquitination enzyme USP46 functions as a tumor suppressor by controlling PHLPP-dependent attenuation of Akt signaling in colon cancer

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

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Cite this