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

作者：Yu‐Chuan Yan, Guang-Xiao Meng, Chuncheng Yang, Yafei Yang, Siyu Tan, Lun‐Jie Yan, Zi‐Niu Ding, Yunlong Ma, Zhao‐Ru Dong, Tao Li · 发表于：Cell Death and Disease · 年份：2023 · DOI：10.1038/s41419-023-05919-5 · 被引用次数：20 · 研究领域：Hippo pathway signaling and YAP/TAZ、Lipid metabolism and biosynthesis、Autophagy in Disease and Therapy

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.