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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Acknowledgements
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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Li, X., Stevens, P., Yang, H. et al. The deubiquitination enzyme USP46 functions as a tumor suppressor by controlling PHLPP-dependent attenuation of Akt signaling in colon cancer. Oncogene 32, 471–478 (2013). https://doi.org/10.1038/onc.2012.66
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DOI: https://doi.org/10.1038/onc.2012.66
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