J Cancer 2021; 12(21):6553-6562. doi:10.7150/jca.61996

Research Paper

The E3 Ubiquitin Ligase HOIP inhibits Cancer Cell Apoptosis via modulating PTEN stability

Zhiguo Niu1,2*, Xin Li2*, Shuxiao Dong3*, Jianhui Gao2, Qingsong Huang2, Huijie Yang2, Hui Qian1, Shu Zhuo4, Ting Zhuang2, Jian Zhu2,5✉, Yinlu Ding5✉, Wenrong Xu1✉

1. Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212000, China.
2. Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, 453000, China.
3. Department of Gastroenterology surgery, Shandong Provincial Third Hospital, Jinan, 250000, China.
4. Signet Therapeutics Inc, Shenzhen, China. Research Institute of Tsinghua University in Shenzhen, Shenzhen, 518000, China.
5. Department of general surgery, the Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250033, China.
*These authors contributed equally to this work.

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Niu Z, Li X, Dong S, Gao J, Huang Q, Yang H, Qian H, Zhuo S, Zhuang T, Zhu J, Ding Y, Xu W. The E3 Ubiquitin Ligase HOIP inhibits Cancer Cell Apoptosis via modulating PTEN stability. J Cancer 2021; 12(21):6553-6562. doi:10.7150/jca.61996. Available from https://www.jcancer.org/v12p6553.htm

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Chemotherapy is widely used in a variety of solid tumors, such as lung cancer, gastric cancer and breast cancer. The genotoxic drugs, such as cisplatin, suppress cancer progression either by inhibition cell proliferation or facilitating apoptosis. However, the chemotherapy resistance remains an urgent challenge in cancer therapy, especially in advanced stages. Several studies showed that the activation of pro-survival pathways, such as PI3K-AKT, participated in mediating chemotherapy resistance. The insights into the molecular mechanisms for underlying chemotherapy resistance are of great importance to improve cancer patient survival in advanced stages. The HOIP protein belongs to the RING family E3 ubiquitin ligases and modulates several atypical ubiquitination processes in cellular signaling. Previous studies showed that HOIP might be an important effector in modulating cancer cell death under genotoxic drugs. Here, we report that HOIP associates with PTEN and facilitates PTEN degradation in cancer cells. Depletion of HOIP causes cell cycle arrest and apoptosis, which effects could be rescued by PTEN silencing. Besides, the survival data from public available database show that HOIP expression correlates with poor survival in several types of chemotherapy-treated cancer patients. In conclusion, our study establishes a novel mechanism by which HOIP modulates PTEN stability and facilitates chemotherapy resistance in malignancies.

Keywords: PTEN, HOIP, Apoptosis, Ubiquitin