HSD17B4 methylation enhances glucose dependence of BT-474 breast cancer cells and increases lapatinib sensitivity.

Autor: Arai N; Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan.; Department of Surgery, Kyorin University School of Medicine, Tokyo, Japan., Hattori N; Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan.; Department of Epigenomics, Institute for Advanced Life Sciences, Hoshi University, Tokyo, Japan., Yamashita S; Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan., Liu YY; Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan.; Department of Epigenomics, Institute for Advanced Life Sciences, Hoshi University, Tokyo, Japan., Ebata T; Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan.; Department of Epigenomics, Institute for Advanced Life Sciences, Hoshi University, Tokyo, Japan., Takeuchi C; Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan.; Department of Epigenomics, Institute for Advanced Life Sciences, Hoshi University, Tokyo, Japan., Takeshima H; Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan.; Department of Epigenomics, Institute for Advanced Life Sciences, Hoshi University, Tokyo, Japan., Fujii S; Department of Molecular Pathology, Yokohama City University Graduate School of Medicine, Kanagawa, Japan., Kondo H; Department of Surgery, Kyorin University School of Medicine, Tokyo, Japan., Mukai H; Department of Medical Oncology, National Cancer Center Hospital East, Chiba, Japan., Ushijima T; Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan. tushijima142@hoshi.ac.jp.; Department of Epigenomics, Institute for Advanced Life Sciences, Hoshi University, Tokyo, Japan. tushijima142@hoshi.ac.jp.
Jazyk: angličtina
Zdroj: Breast cancer research and treatment [Breast Cancer Res Treat] 2023 Sep; Vol. 201 (2), pp. 317-328. Date of Electronic Publication: 2023 Jun 28.
DOI: 10.1007/s10549-023-07013-y
Abstrakt: Purpose: HER2-positive breast cancer has a high chance of achieving pathological complete response when HSD17B4, responsible for peroxisomal β-oxidation of very long-chain fatty acids (VLCFA) and estradiol, is methylation-silenced. Here, we aimed to identify the underlying molecular mechanism.
Methods: Using a HER2-positive breast cancer cell line, BT-474, control and knock-out (KO) clones were obtained. Metabolic characteristics were analyzed using a Seahorse Flux analyzer.
Results: HSD17B4 KO suppressed cellular proliferation, and enhanced sensitivity to lapatinib approximately tenfold. The KO led to accumulation of VLCFA and a decrease of polyunsaturated fatty acids (PUFAs), such as docosahexaenoic acid (DHA) and arachidonic acid. HSD17B4 KO increased Akt phosphorylation, possibly via decreased DHA, and genes involved in oxidative phosphorylation (OxPhos) and electron transport chain (ETC) were upregulated. Increased mitochondrial ATP production in the KO cells was confirmed by extracellular flux analyzer. Increased OxPhos led to severe dependence of the KO cells on pyruvate from glycolysis. Suppression of glycolysis by lapatinib led to severe delayed suppression of OxPhos in KO cells.
Conclusion: HSD17B4 KO in BT-474 cells caused a decrease of PUFAs, increased Akt phosphorylation, enhanced glucose dependence of OxPhos, and increased sensitivity to inhibition of HER2, upstream of Akt. This mechanism may be applicable to other HER2-positive glucose-dependent breast cancer cells with HSD17B4 silencing.
(© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
Databáze: MEDLINE
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