Hypoxia is a feature of solid tumors. Most tumors are at least partially hypoxic. This hypoxic environment plays a critical role in promoting resistance to anticancer drugs. PHLPP, a novel family of Ser/Thr protein phosphatases, functions as a tumor suppressor by negatively regulating Akt signaling in colon cancer. Here, we show that the expression of both PHLPP isoforms is negatively regulated by hypoxia in colon cancer cells. Hypoxia-induced decrease of PHLPP expression is attenuated by silencing HIF-1α but not HIF-2α, indicating that PHLPP downregulation is HIF-1α-dependent. Whereas the mRNA levels of PHLPP are not significantly altered in hypoxia, the reduction of PHLPP expression is caused by decreased protein translation downstream of mTOR and increased protein degradation. Specifically, hypoxia-induced downregulation of PHLPP is partially rescued in TSC2 or 4E-BP1 knockdown cells as the result of elevated levels of mTOR activity and protein synthesis. In addition, we show that hypoxia promotes PHLPP degradation by increasing the mRNA expression of USP46, a PHLPP-specific deubiquitinase, and resulting in upregulation of PHLPP ubiquitination. Functionally, downregulation of PHLPP plays an important role in hypoxia-induced chemoresistance in colon cancer cells. Taken together, we have identified hypoxia as a novel mechanism by which PHLPP is downregulated in colon cancer, and the expression of PHLPP may serve as a biomarker for better understand the drug resistance in cancer treatment.

Citation Format: Yang-an Wen, Tianyan Gao. Downregulation of PHLLP expression contributes to hypoxia-induced resistance to chemotherapy in colon cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5204. doi:10.1158/1538-7445.AM2013-5204