期刊
CANCER LETTERS
卷 502, 期 -, 页码 154-165出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2020.12.019
关键词
Hepatocellular carcinoma; ACSL4; Lipogenesis; SREBP1
类别
资金
- Zhejiang Provincial Natural Science Foundation [LY21H160019]
- National Natural Science Foundation of China [81874228, 81902410]
- Innovative Research Groups of National Natural Science Foundation of China [81721091]
- National ST Major Project [2017ZX10203205]
- Zhejiang International Science and Technology Cooperation Project [2016C04003]
- Research Unit Project of Chinese Academy of Medical Sciences [2019-I2M-5-030]
- Major program of National Natural Science Foundation of China [91542205]
Lipid metabolic reprogramming is crucial for hepatocellular carcinoma (HCC) development, with long chain acyl CoA synthetase 4 (ACSL4) playing a key role in modulating de novo lipogenesis and promoting HCC progression. Mechanistically, ACSL4 upregulates SREBP1 to regulate lipogenesis in HCC cells, with a positive correlation between ACSL4 and SREBP1 expression in HCC patients, suggesting a potential combinational biomarker for predicting HCC.
Lipid metabolic reprogramming plays a pivotal role in hepatocellular carcinoma (HCC) development, but the underlying mechanisms are incompletely characterized. Long chain acyl CoA synthetase 4 (ACSL4), a member of acyl-CoA synthetases (ACS) family, has been identified as a novel marker of alpha-fetoprotein-high subtype HCC and as an oncogene. Here, we identified a new function of ACSL4 in HCC lipid metabolism. ACSL4 can modulate de novo lipogenesis by accumulating intracellular triglycerides, cholesterols, and lipid droplets in HCC. Mechanistically, ACSL4 upregulates the master lipogenesis regulator sterol regulatory element binding protein 1 (SREBP1) and its downstream lipogenic enzymes in HCC cells via c-Myc. Moreover, SREBP1 is crucial for ACSL4-mediated regulation of lipogenesis as well as HCC cell proliferation and metastasis, as SREBP1 overexpression rescues lipogenic deficiency and decreased oncogenic capabilities associated with ACSL4 suppression in vitro and in vivo. Clinically, our data showed that the expression of ACSL4 was positively correlated with that of SREBP1 in HCC patients, and the combinational biomarkers showed strong predictive value for HCC. Together, our findings uncover a new mechanism by which ACSL4 modulates aberrant lipid metabolism and promotes the progression of HCC.
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