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TET2 deficiency sensitizes tumor cells to statins by reducing HMGCS1 expression

Oncogene volume 41, pages 5385–5396 (2022)Cite this article

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Abstract

TET2 (ten-eleven-translocation) protein is a Fe(II)- and α-ketoglutarate-dependent dioxygenase that catalyzes DNA demethylation to regulate gene expression. While TET2 gene is frequently mutated in hematological cancer, its enzymatic activity is also compromised in various solid tumors. Whether TET2 deficiency creates vulnerability for cancer cells has not been studied. Here we reported that TET2 deficiency is associated with the change of lipid metabolism processes in acute myeloid leukemia (AML) patient. We demonstrate that statins, the inhibitors of β-Hydroxy β-methylglutaryl-CoA (HMG-CoA) reductase and commonly used cholesterol-lowering medicines, significantly sensitize TET2 deficient tumor cells to apoptosis. TET2 directly regulates the expression of HMG-CoA synthase (HMGCS1) by catalyzing demethylation on its promoter region, and conversely TET2 deficiency leads to significant down-regulation of HMGCS1 expression and the mevalonate pathway. Consistently, overexpression of HMGCS1 in TET2-deficient cells rescues statin-induced apoptosis. We further reveal that decrease of geranylgeranyl diphosphate (GGPP), an intermediate metabolite in the mevalonate pathway, is responsible for statin-induced apoptosis. GGPP shortage abolishes normal membrane localization and function of multiple small GTPases, leading to cell dysfunction. Collectively, our study reveals a vulnerability in TET2 deficient tumor and a potential therapeutic strategy using an already approved safe medicine.

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Fig. 1: TET2 aberrations affect lipid and carbohydrate metabolism pathways.
Fig. 2: TET2 deficiency sensitizes cells to statin-induced apoptosis in multiple cancer cell types.
Fig. 3: Loss of TET2 attenuates the mevalonate pathway.
Fig. 4: TET2 regulates the cholesterol synthesis pathway by promoting HMGCS1 expression.
Fig. 5: Addition of MVA or GGPP rescues the lovastatin-mediated apoptosis in TET2 KO cells.
Fig. 6: Combination of TET2 loss and Lovastatin treatment reduce the membrane localization of small GTPases.
Fig. 7: Model of TET2 sensitizes tumor cells to statins by reducing HMGCS1 expression.

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Acknowledgements

This work was supported by the National Key Research and Development Project of China (No. 2018YFA0800304 to H.-X.Y.), the NSFC grants (No. 82172595 to H.-X.Y.), and the Development Fund for Shanghai Talents (No. 2019109 to H.-X.Y.). H.-X.Y. is also supported by the Supporting Fund for Innovation and Entrepreneurship by Chongqing Returned Oversea Scholars.

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Author notes

  1. These authors contributed equally: Si-Jia Sun, Ying-Jie Ai.

Authors and Affiliations

  1. The Fifth People’s Hospital of Shanghai, Molecular and Cell Biology Research Lab of the Institutes of Biomedical Sciences, Shanghai College of Medicine, Fudan University, Shanghai, China

    Si-Jia Sun, Kun-Long Duan, Jin-Ye Zhang, Cheng Zhang, Yi-Ping Sun & Hai-Xin Yuan

  2. Department of Gastroenterology and Hepatology, Zhongshan Hospital, Shanghai College of Medicine, Fudan University, Shanghai, China

    Ying-Jie Ai

  3. Cullgen Inc. 12730 High Bluff Drive, San Diego, CA92130, CA, USA

    Yue Xiong

  4. Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, San Diego, 92093, CA, USA

    Kun-Liang Guan

  5. Center for Novel Target and Therapeutic Intervention, Institute of Life Sciences, Chongqing Medical University, Chongqing, 400016, China

    Hai-Xin Yuan

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Contributions

S-JS, YX, K-LG and H-XY conceived the general framework of this study. Y-JA contributed to the bioinformatics analysis. S-JS, Y-JA and H-XY designed the experiments. S-JS, Y-JA, K-LD, J-YZ, CZ and Y-PS performed experiments. S-JS, Y-JA, YX, K-LG and H-XY prepared the manuscript.

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Correspondence to Hai-Xin Yuan.

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Competing interests

KLG is a co-founder of Vivace Therapeutics. YX is a co-founder of Cullgen Inc. Other authors declare no competing financial interests.

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Sun, SJ., Ai, YJ., Duan, KL. et al. TET2 deficiency sensitizes tumor cells to statins by reducing HMGCS1 expression. Oncogene 41, 5385–5396 (2022). https://doi.org/10.1038/s41388-022-02531-3

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