ABHD5 blunts the sensitivity of colorectal cancer to fluorouracil via promoting autophagic uracil yield

Juanjuan Ou (), Yuan Peng, Weiwen Yang, Yue Zhang, Jie Hao, Fu Li, Yanrong Chen, Yang Zhao, Xiong Xie, Shuang Wu, Lin Zha, Xi Luo, Ganfeng Xie, Liting Wang, Wei Sun, Qi Zhou, Jianjun Li () and Houjie Liang ()
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Juanjuan Ou: Army Medical University
Yuan Peng: Army Medical University
Weiwen Yang: Army Medical University
Yue Zhang: Army Medical University
Jie Hao: Army Medical University
Fu Li: Army Medical University
Yanrong Chen: Army Medical University
Yang Zhao: Army Medical University
Xiong Xie: Army Medical University
Shuang Wu: Army Medical University
Lin Zha: Army Medical University
Xi Luo: Army Medical University
Ganfeng Xie: Army Medical University
Liting Wang: Army Medical University
Wei Sun: Army Medical University
Qi Zhou: Fuling Central Hospital
Jianjun Li: Army Medical University
Houjie Liang: Army Medical University

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract The efficacy of Fluorouracil (FU) in the treatment of colorectal cancer (CRC) is greatly limited by drug resistance. Autophagy has been implicated in chemoresistance, but the role of selective autophagic degradation in regulating chemoresistance remains unknown. In this study, we revealed a critical role of ABHD5 in charging CRC sensitivity to FU via regulating autophagic uracil yield. We demonstrated that ABHD5 localizes to lysosome and interacts with PDIA5 to prevent PDIA5 from interacting with RNASET2 and inactivating RNASET2. ABHD5 deficiency releases PDIA5 to directly interact with RNASET2 and leave RNASET2 in an inactivate state, which impairs RNASET2-mediated autophagic uracil yield and promotes CRC cells to uptake FU as an exogenous uracil, thus increasing their sensitivity to FU. Our findings for the first time reveal a novel role of ABHD5 in regulating lysosome function, highlighting the significance of ABHD5 as a compelling biomarker predicting the sensitivity of CRCs to FU-based chemotherapy.

Date: 2019
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DOI: 10.1038/s41467-019-08902-x

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