Diacylglycerol lipase alpha promotes hepatocellular carcinoma progression and induces lenvatinib resistance by enhancing YAP activity

As an important hydrolytic enzyme that yields 2-AG and free fatty acids, diacylglycerol lipase alpha (DAGLA) is involved in exacerbating malignant phenotypes and cancer progression, but the role of the DAGLA/2-AG axis in HCC progression remains unclear. Here, we found that the upregulation of compon...

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Published in:Cell death & disease 2023-07, Vol.14 (7), p.404-404, Article 404
Main Authors: Yan, Yu-Chuan, Meng, Guang-Xiao, Yang, Chun-Cheng, Yang, Ya-Fei, Tan, Si-Yu, Yan, Lun-Jie, Ding, Zi-Niu, Ma, Yun-Long, Dong, Zhao-Ru, Li, Tao
Format: Article
Language:English
Subjects:
1-Phosphatidylinositol 3-kinase
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AKT protein
Antibodies
Biochemistry
Biomedical and Life Sciences
Cell Biology
Cell Culture
Cell proliferation
Diglycerides
Fatty acids
Hepatocellular carcinoma
Immunology
Life Sciences
Lipase
Lipoprotein lipase
Liver cancer
Metastases
Nuclear transport
Phenotypes
Phosphorylation
Yes-associated protein
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Summary:As an important hydrolytic enzyme that yields 2-AG and free fatty acids, diacylglycerol lipase alpha (DAGLA) is involved in exacerbating malignant phenotypes and cancer progression, but the role of the DAGLA/2-AG axis in HCC progression remains unclear. Here, we found that the upregulation of components of the DAGLA/2-AG axis in HCC samples is correlated with tumour stage and patient prognosis. In vitro and in vivo experiments demonstrated that the DAGLA/2-AG axis promoted HCC progression by regulating cell proliferation, invasion and metastasis. Mechanistically, the DAGLA/2AG axis significantly inhibited LATS1 and YAP phosphorylation, promoted YAP nuclear translocation and activity, and ultimately led to TEAD2 upregulation and increased PHLDA2 expression, which could be enhanced by DAGLA/2AG-induced activation of the PI3K/AKT pathway. More importantly, DAGLA induced resistance to lenvatinib therapy during HCC treatment. Our study demonstrates that inhibiting the DAGLA/2-AG axis could be a novel therapeutic strategy to inhibit HCC progression and enhance the therapeutic effects of TKIs, which warrant further clinical studies.
ISSN:2041-4889
2041-4889
DOI:10.1038/s41419-023-05919-5