Integrative analysis of mitochondrial metabolic reprogramming in early-stage colon and liver cancer

Yeongmin Kim; So-Yeon Shin; Jihun Jeung; Yumin Kim; Yun-Won Kang; Sunjae Lee; Chang-Myung Oh

doi:10.3389/fonc.2023.1218735

Integrative analysis of mitochondrial metabolic reprogramming in early-stage colon and liver cancer

Front Oncol. 2023 Aug 24:13:1218735. doi: 10.3389/fonc.2023.1218735. eCollection 2023.

Authors

Yeongmin Kim¹, So-Yeon Shin¹, Jihun Jeung², Yumin Kim¹, Yun-Won Kang¹, Sunjae Lee², Chang-Myung Oh¹

Affiliations

¹ Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea.
² Department of School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea.

Abstract

Gastrointestinal malignancies, including colon adenocarcinoma (COAD) and liver hepatocellular carcinoma (LIHC), remain leading causes of cancer-related deaths worldwide. To better understand the underlying mechanisms of these cancers and identify potential therapeutic targets, we analyzed publicly accessible Cancer Genome Atlas datasets of COAD and LIHC. Our analysis revealed that differentially expressed genes (DEGs) during early tumorigenesis were associated with cell cycle regulation. Additionally, genes related to lipid metabolism were significantly enriched in both COAD and LIHC, suggesting a crucial role for dysregulated lipid metabolism in their development and progression. We also identified a subset of DEGs associated with mitochondrial function and structure, including upregulated genes involved in mitochondrial protein import and respiratory complex assembly. Further, we identified mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (HMGCS2) as a crucial regulator of cancer cell metabolism. Using a genome-scale metabolic model, we demonstrated that HMGCS2 suppression increased glycolysis, lipid biosynthesis, and elongation while decreasing fatty acid oxidation in colon cancer cells. Our study highlights the potential contribution of dysregulated lipid metabolism, including ketogenesis, to COAD and LIHC development and progression and identifies potential therapeutic targets for these malignancies.

Keywords: 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2); colon cancer; hepatocellular carcinoma; metabolic reprogramming; mitochondria.

Grants and funding

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2020R1C1C1004999) and “GIST Research Institute IIBR” grants funded by the GIST in 2022.