Yin Yang 1 facilitates hepatocellular carcinoma cell lipid metabolism and tumor progression by inhibiting PGC-1β-induced fatty acid oxidation

Yanjun Li; Vivi Kasim; Xuesong Yan; Lang Li; Ian Timothy Sembiring Meliala; Can Huang; Zhuolin Li; Ke Lei; Guanbin Song; Xiaodong Zheng; Shourong Wu

doi:10.7150/thno.34931

Yin Yang 1 facilitates hepatocellular carcinoma cell lipid metabolism and tumor progression by inhibiting PGC-1β-induced fatty acid oxidation

Theranostics. 2019 Oct 14;9(25):7599-7615. doi: 10.7150/thno.34931. eCollection 2019.

Authors

Yanjun Li^{1

2}, Vivi Kasim^{1

2

3}, Xuesong Yan^{1

2}, Lang Li^{1

2}, Ian Timothy Sembiring Meliala^{1

2}, Can Huang^{1

2}, Zhuolin Li^{1

2}, Ke Lei^{1

2}, Guanbin Song^{1

2}, Xiaodong Zheng⁴, Shourong Wu^{1

2

3}

Affiliations

¹ The Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China.
² The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing 400044, China.
³ State and Local Joint Engineering Laboratory for Vascular Implants, Chongqing University, Chongqing 400044, China.
⁴ Chongqing University Cancer Hospital, Chongqing University, Chongqing 400030, China.

Abstract

Lipid accumulation is a driving force in tumor development, as it provides tumor cells with both energy and the building blocks of phospholipids for construction of cell membranes. Aberrant homeostasis of lipid metabolism has been observed in various tumors; however, the molecular mechanism has not been fully elucidated. Methods: Yin yang 1 (YY1) expression in hepatocellular carcinoma (HCC) was analyzed using clinical specimens, and its roles in HCC in lipid metabolism were examined using gain- and loss-of function experiments. The mechanism of YY1 regulation on peroxisome proliferator-activated receptor gamma coactivator-1β (PGC-1β) and its downstream genes medium-chain acyl-CoA dehydrogenase (MCAD) and long-chain acyl-CoA dehydrogenase (LCAD) were investigated using molecular biology and biochemical methods. The role of YY1/ PGC-1β axis in hepatocarcinogenesis was studied using xenograft experiment. Results: This study showed that YY1 suppresses fatty acid β-oxidation, leading to increase of cellular triglyceride level and lipid accumulation in HCC cells, and subsequently induction of the tumorigenesis potential of HCC cells. Molecular mechanistic study revealed that YY1 blocks the expression of PGC-1β, an activator of fatty acid β-oxidation, by directly binding to its promoter; and thus downregulates PGC-1β/MCAD and PGC1-β/LCAD axis. Importantly, we revealed that YY1 inhibition on PGC-1β occurs irrespective of the expression of hypoxia-inducible factor-1α (HIF1-α), enabling it to promote lipid accumulation under both normoxic and hypoxic conditions. Conclusion: Our study reveals the critical role of YY1/PGC-1β axis in HCC cell lipid metabolism, providing novel insight into the molecular mechanisms associated with tumor cell lipid metabolism, and a new perspective regarding the function of YY1 in tumor progression. Thus, our study provides evidences regarding the potential of YY1 as a target for lipid metabolism-based anti-tumor therapy.

Keywords: PGC-1β; Yin Yang 1; fatty acid oxidation; hepatocellular carcinoma; lipid accumulation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carcinogenesis / metabolism
Carcinoma, Hepatocellular / genetics
Carcinoma, Hepatocellular / metabolism*
Cell Line, Tumor
Down-Regulation / genetics
Fatty Acids / metabolism*
Humans
Lipid Metabolism / genetics
Lipid Metabolism / physiology*
Liver Neoplasms / genetics
Liver Neoplasms / metabolism*
Male
Mice
Mice, Inbred BALB C
Mice, Nude
Oxidation-Reduction
Promoter Regions, Genetic / genetics
RNA-Binding Proteins / metabolism*
YY1 Transcription Factor / metabolism*

Substances

Fatty Acids
PPARGC1B protein, human
RNA-Binding Proteins
YY1 Transcription Factor
YY1 protein, human