Down-regulation of BMAL1 by MiR-494-3p Promotes Hepatocellular Carcinoma Growth and Metastasis by Increasing GPAM-mediated Lipid Biosynthesis

The circadian clock confers daily rhythmicity to many crucial biological processes and behaviors and its disruption is closely associated with carcinogenesis in several types of cancer. Brain and muscle arnt-like protein 1 (BMAL1) is a core circadian rhythm component in mammals and its dysregulation...

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Published in:International journal of biological sciences 2022-01, Vol.18 (16), p.6129-6144
Main Authors: Yang, Yi, Yang, Tao, Zhao, Zifeng, Zhang, Hongxin, Yuan, Peng, Wang, Gang, Zhao, Zheng, An, Jiaze, Lyu, Zhuomin, Xing, Jinliang, Li, Jibin
Format: Article
Language:English
Subjects:
Acyltransferase
Anti-oncogenes
Apoptosis
Biological activity
Biological clocks
Biosynthesis
BMAL1 protein
Cancer
Carcinogenesis
Carcinogens
Cell cycle
Cell growth
Circadian rhythm
Circadian rhythms
Flow cytometry
Gene expression
Glycerol
Glycerol-3-phosphate
Hepatocellular carcinoma
Lipid metabolism
Lipids
Liver cancer
Lysophosphatidic acid
Medical prognosis
Metabolism
Metastases
Metastasis
Mitochondria
Muscles
Ovarian cancer
Proteins
Survival analysis
Tumorigenesis
Tumors
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Summary:The circadian clock confers daily rhythmicity to many crucial biological processes and behaviors and its disruption is closely associated with carcinogenesis in several types of cancer. Brain and muscle arnt-like protein 1 (BMAL1) is a core circadian rhythm component in mammals and its dysregulation has been shown to contribute to aberrant metabolism in human diseases. However, the biological functions of BMAL1, especially its involvement in aberrant lipid metabolism in hepatocellular carcinoma (HCC), remain elusive. In the present study, we found that BMAL1 was frequently down-regulated in HCC cells mainly due to the up-regulation of miR-494-3p. Down-regulation of BMAL1 was significantly associated with poor survival in HCC patients. BMAL1 down-regulation promoted HCC cell growth and metastasis both in vitro and in vivo. Mechanistically, through cooperating with EZH2, BMAL1 transcriptionally suppressed the expression of glycerol-3-phosphate acyltransferase mitochondrial (GPAM), a key enzyme involved in the regulation of lipid biosynthesis, leading to reduced levels lysophosphatidic acid (LPA), which have long been known as mediator of oncogenesis. Particularly, treatment with SR8278, an activator of BMAL1, exhibited a therapeutic effect on HCC in vitro and in vivo. In conclusion, BMAL1 plays a critical anti-oncogenic role in HCC, providing strong research evidence for BMAL1 as a prospective target for HCC therapy.
ISSN:1449-2288
1449-2288
DOI:10.7150/ijbs.74951