Dysregulated lipid metabolism blunts the sensitivity of cancer cells to EZH2 inhibitor
Tengrui Zhang,
Zhengyang Guo,
Xiao Huo,
Yueqing Gong,
Chen Li,
Jiaqi Huang,
Yan Wang,
Hao Feng,
Xiaojuan Ma,
Changtao Jiang,
Qianqian Yin,
Lixiang Xue
Affiliations
Tengrui Zhang
Department of Radiation Oncology, Peking University Third Hospital Cancer Center, Peking University Third Hospital, Beijing 100191, China
Zhengyang Guo
Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, China
Xiao Huo
Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, China
Yueqing Gong
Department of Gastroenterology, Peking University Third Hospital, Beijing 100191, China
Chen Li
Department of Radiation Oncology, Peking University Third Hospital Cancer Center, Peking University Third Hospital, Beijing 100191, China
Jiaqi Huang
Department of Radiation Oncology, Peking University Third Hospital Cancer Center, Peking University Third Hospital, Beijing 100191, China
Yan Wang
Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, China
Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, China
Changtao Jiang
Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, China; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University, Beijing 100191, China
Qianqian Yin
Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, China; Corresponding author at: Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, China.
Lixiang Xue
Department of Radiation Oncology, Peking University Third Hospital Cancer Center, Peking University Third Hospital, Beijing 100191, China; Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, China; Corresponding author at: Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, China.
Summary: Background: Sensitivity has been a key issue for Enhancer of zeste homolog 2 (EZH2) inhibitors in cancer therapy. The EZH2 inhibitor EPZ-6438 was first approved by the US Food and Drug Administration (FDA) in 2020. However, its inadequate anti-cancer activity in solid tumors limits its clinical application. In this study, we utilized the multiple cancer cell lines, which are less sensitive to the EZH2 inhibitor GSK126, combining animal model and clinical data to investigate the underlying mechanism. Methods: IncuCyte S3 was used to explore the difference in the responsiveness of hematological tumor cells and solid tumor cells to GSK126. Transcriptome and metabolome of B16F10 cells after GSK126 treatment were analyzed and the distinct changes in the metabolic profile were revealed. Real-time quantitative PCR and western blot experiments were used to further verify the multi-omics data. ChIP-qPCR was performed to detected H3K27me3 enrichment of target genes. Finally, the anti-tumor effects of combining GSK126 and lipid metabolism drugs were observed with IncuCyte S3 platform, CCK-8 and animal model respectively. Findings: We found that although the proliferative phenotype did not show strong difference upon treatment with GSK126, the transcriptome and metabolome changed profoundly. GSK126 treatment led to broad shifts in glucose, amino acid, and lipid metabolism. Lipid synthesis was strengthened manifested by the increasing abundance of unsaturated fatty acids. SCD1 and ELOVL2 were regulated by H3K27me3 at gene regulatory region, and upregulated by EZH2 knockdown and inhibitors. SCD1 knockdown increased cellular sensitivity to GSK126. Based on the findings above, the application of the combination with SCD1 inhibitor significantly attenuated the proliferation of cancer and increased the sensitivity to GSK126 by suppressing desaturation of fatty acids. Interpretation: Dysregulated lipid metabolism can blunt the sensitivity of cancer cells to GSK126. These characteristics shed light on the novel combination therapy strategies to combat tumor resistance. Funding: National Natural Science Foundation of China (No. 81672091, No.91749107 and No. 81972966).
