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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 &, 2019. "ABHD5 blunts the sensitivity of colorectal cancer to fluorouracil via promoting autophagic uracil yield," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-08902-x
    DOI: 10.1038/s41467-019-08902-x
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