DUSP16 promotes cancer chemoresistance through regulation of mitochondria-mediated cell death

Heng Boon Low, Zhen Lim Wong, Bangyuan Wu, Li Ren Kong, Chin Wen Png, Yik-Lam Cho, Chun-Wei Li, Fengchun Xiao, Xuan Xin, Henry Yang, Jia Min Loo, Fiona Yi Xin Lee, Iain Bee Huat Tan, Ramanuj DasGupta, Han-Ming Shen, Herbert Schwarz, Nicholas R. J. Gascoigne, Boon Cher Goh, Xiaohong Xu () and Yongliang Zhang ()
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Heng Boon Low: National University of Singapore
Zhen Lim Wong: National University of Singapore
Bangyuan Wu: National University of Singapore
Li Ren Kong: National University of Singapore
Chin Wen Png: National University of Singapore
Yik-Lam Cho: National University of Singapore
Chun-Wei Li: The First Affiliated Hospital of Sun Yat-Sen University
Fengchun Xiao: The First Affiliated Hospital of Zhejiang Chinese Medical University
Xuan Xin: National University of Singapore
Henry Yang: National University of Singapore
Jia Min Loo: Genome Institute of Singapore, Agency of Science Technology and Research (A*Star)
Fiona Yi Xin Lee: National Cancer Center
Iain Bee Huat Tan: National Cancer Center
Ramanuj DasGupta: Genome Institute of Singapore, Agency of Science Technology and Research (A*Star)
Han-Ming Shen: National University of Singapore
Herbert Schwarz: National University of Singapore
Nicholas R. J. Gascoigne: National University of Singapore
Boon Cher Goh: National University of Singapore
Xiaohong Xu: The First Affiliated Hospital of Zhejiang Chinese Medical University
Yongliang Zhang: National University of Singapore

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract Drug resistance is a major obstacle to the treatment of most human tumors. In this study, we find that dual-specificity phosphatase 16 (DUSP16) regulates resistance to chemotherapy in nasopharyngeal carcinoma, colorectal cancer, gastric and breast cancer. Cancer cells expressing higher DUSP16 are intrinsically more resistant to chemotherapy-induced cell death than cells with lower DUSP16 expression. Overexpression of DUSP16 in cancer cells leads to increased resistance to cell death upon chemotherapy treatment. In contrast, knockdown of DUSP16 in cancer cells increases their sensitivity to treatment. Mechanistically, DUSP16 inhibits JNK and p38 activation, thereby reducing BAX accumulation in mitochondria to reduce apoptosis. Analysis of patient survival in head & neck cancer and breast cancer patient cohorts supports DUSP16 as a marker for sensitivity to chemotherapy and therapeutic outcome. This study therefore identifies DUSP16 as a prognostic marker for the efficacy of chemotherapy, and as a therapeutic target for overcoming chemoresistance in cancer.

Date: 2021
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DOI: 10.1038/s41467-021-22638-7

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