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Int J Biol Sci 2023; 19(7):2114-2131. doi:10.7150/ijbs.82177 This issue Cite

Research Paper

Bulk and single-cell transcriptome profiling reveal extracellular matrix mechanical regulation of lipid metabolism reprograming through YAP/TEAD4/ACADL axis in hepatocellular carcinoma

Jingwei Cai^1,2,3,4,#, Tianyi Chen^1,2,3,4,#, Zhiyu Jiang^1,2,3,4,#, Jiafei Yan^1,2,3,4, Zhengtao Ye^1,2,3,4, Yeling Ruan^1,2,3,4, Liye Tao^1,2,3,4, Zefeng Shen^1,2,3,4, Xiao Liang^1,2,3,4, Yifan Wang^1,2,3,4, Junjie Xu^1,2,3,4,✉, Xiujun Cai^1,2,3,4,✉

1. Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, 310016, Hangzhou, China.
2. Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment 310016, Hangzhou, China.
3. Zhejiang University Cancer Center, 310058, Hangzhou, China.
4. Liangzhu Laboratory, Zhejiang University Medical Center, 311121, Hangzhou, China.
^#These authors contributed equally.

✉ Corresponding authors: Prof. Xiujun Cai. E-mail: srrsh_cxjedu.cn. Dr. Junjie Xu. E-mail: walter235edu.cn.

Abstract

Emerging studies have revealed matrix stiffness promotes hepatocellular carcinoma (HCC) development. We studied metabolic dysregulation in HCC using the TCGA-LIHC database (n=374) and GEO datasets (GSE14520). HCC samples were classified into three heterogeneous metabolic pathway subtypes with different metabolic profiles: Cluster 1, an ECM-producing subtype with upregulated glycan metabolism; Cluster 2, a hybrid subtype with partial pathway dysregulation. Cluster 3, a lipogenic subtype with upregulated lipid metabolism; These three subtypes have different prognosis, clinical features and genomic alterations. We identified key enzymes that respond to matrix stiffness and regulate lipid metabolism through bioinformatic analysis. We found long-chain acyl-CoA dehydrogenase (ACADL) is a mechanoreactive enzyme that reprograms HCC cell lipid metabolism in response to extracellular matrix stiffness. ACADL is also regarded as tumor suppressor in HCC. We found that increased extracellular matrix stiffness led to activation of Yes-associated protein (YAP) and the YAP/TEA Domain transcription factor 4 (TEAD4) transcriptional complex was able to directly repress ACADL at the transcriptional level. The ACADL-dependent mechanoresponsive pathway is a potential therapeutic target for HCC treatment.

Keywords: Hepatocellular carcinoma, extracellular matrix, ACADL, YAP

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