ABHD5 inhibits YAP-induced c-Met overexpression and colon cancer cell stemness via suppressing YAP methylation

Yan Gu, Yanrong Chen, Lai Wei, Shuang Wu, Kaicheng Shen, Chengxiang Liu, Yan Dong, Yang Zhao, Yue Zhang, Chi Zhang, Wenling Zheng, Jiangyi He, Yunlong Wang, Yifei Li, Xiaoxin Zhao, Hongwei Wang, Jun Tan, Liting Wang, Qi Zhou (), Ganfeng Xie (), Houjie Liang () and Juanjuan Ou ()
Additional contact information
Yan Gu: Third Military Medical University (Army Medical University)
Yanrong Chen: Third Military Medical University (Army Medical University)
Lai Wei: Third Military Medical University (Army Medical University)
Shuang Wu: Third Military Medical University (Army Medical University)
Kaicheng Shen: Third Military Medical University (Army Medical University)
Chengxiang Liu: Third Military Medical University (Army Medical University)
Yan Dong: Third Military Medical University (Army Medical University)
Yang Zhao: Third Military Medical University (Army Medical University)
Yue Zhang: Third Military Medical University (Army Medical University)
Chi Zhang: Third Military Medical University (Army Medical University)
Wenling Zheng: Third Military Medical University (Army Medical University)
Jiangyi He: Third Military Medical University (Army Medical University)
Yunlong Wang: Third Military Medical University (Army Medical University)
Yifei Li: Third Military Medical University (Army Medical University)
Xiaoxin Zhao: Third Military Medical University (Army Medical University)
Hongwei Wang: Third Military Medical University (Army Medical University)
Jun Tan: Third Military Medical University (Army Medical University)
Liting Wang: Third Military Medical University (Army Medical University)
Qi Zhou: Fuling Central Hospital of Chongqing City
Ganfeng Xie: Third Military Medical University (Army Medical University)
Houjie Liang: Third Military Medical University (Army Medical University)
Juanjuan Ou: Third Military Medical University (Army Medical University)

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract Cancer stemness represents a major source of development and progression of colorectal cancer (CRC). c-Met critically contributes to CRC stemness, but how c-Met is activated in CRC remains elusive. We previously identified the lipolytic factor ABHD5 as an important tumour suppressor gene in CRC. Here, we show that loss of ABHD5 promotes c-Met activation to sustain CRC stemness in a non-canonical manner. Mechanistically, we demonstrate that ABHD5 interacts in the cytoplasm with the core subunit of the SET1A methyltransferase complex, DPY30, thereby inhibiting the nuclear translocation of DPY30 and activity of SET1A. In the absence of ABHD5, DPY30 translocates to the nucleus and supports SET1A-mediated methylation of YAP and histone H3, which sequesters YAP in the nucleus and increases chromatin accessibility to synergistically promote YAP-induced transcription of c-Met, thus promoting the stemness of CRC cells. This study reveals a novel role of ABHD5 in regulating histone/non-histone methylation and CRC stemness.

Date: 2021
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DOI: 10.1038/s41467-021-26967-5

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