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A novel KDM5A/MPC-1 signaling pathway promotes pancreatic cancer progression via redirecting mitochondrial pyruvate metabolism

Oncogene volume 39, pages 1140–1151 (2020)Cite this article

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Abstract

Mitochondrial pyruvate carrier 1 (MPC-1) appears to be a tumor suppressor. In this study, we determined the regulation of MPC-1 expression by Lysine demethylase 5A (KDM5A) and critical impact of this novel KDM5A/MPC-1 signaling on PDA progression. TCGA database, paired PDA and adjacent normal pancreatic tissues, PDA tissue array and cell lines were used to determine the levels of MPC-1 and KDM5A expression, and their relationship with the clinicopathologic characteristics and overall survival (OS) of PDA patients. Both in vitro and in vivo models were used to determine biologic impacts of MPC-1 and KDM5A on PDA and mitochondrial pyruvate metabolism, and the mechanism underling reduced MPC-1 expression in PDA. The expression of MPC-1 was decreased in PDA cell lines and tissues, and negatively associated with tumor poorer differentiation, lymph nodes metastasis, higher TNM stages, and patients’ overall survival (OS). Functional analysis revealed that restored expression of MPC-1 suppressed the growth, invasion, migration, stemness and tumorigenicity. Re-expression of MPC-1 stimulated the mitochondrial pyruvate metabolism and inhibited glycolysis, while MPC-1-specific inhibitor UK5099 attenuated these effects. Furthermore, KDM5A bound directly to MPC-1 promoter region and transcriptionally suppressed the expression of MPC-1 via demethylation H3K4. Consistently, KDM5A expression was elevated in PDA and promoted PDA cell proliferation in vitro and tumor growth in vivo via suppressing the expression of MPC-1. The expression of KDM5A was inversely correlated with that of MPC-1 in PDA. KDM5A/MPC-1 signaling promoted PDA growth, invasion, migration, and stemness via inhibiting mitochondrial pyruvate metabolism. Targeting KDM5A/MPC-1 signaling may be an effective therapeutic strategy for PDA.

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Funding

This work was supported by grants 81502018 (to JC), 81502043 (to MQ) and 81602051 (to DX) from National Natural Science Foundation of China; grant [2019]72 (to JC) from Shanghai “Rising Stars of Medical Talent” Youth Development Program, Youth Medical Talents-Specialist Program; Fundamental Research Funds for the Central Universities 22120180029 (to MQ); The Outstanding Clinical Discipline Project of Shanghai Pudong (Grant No. PWYgy2018-02).

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Author notes

  1. These authors contributed equally: Jiujie Cui, Quan Ming, Dacheng Xie

Authors and Affiliations

  1. Department of Medical Oncology, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China

    Jiujie Cui

  2. State Key Laboratory of Oncogene and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China

    Jiujie Cui

  3. Department of Oncology and Tumor Institute, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China

    Ming Quan, Dacheng Xie, Yong Gao & Jingde Chen

  4. Department of Medicine, The University of Arizona College of Medicine at Phoenix, Phoenix, USA

    Sushovan Guha, Michael B. Fallon & Keping Xie

  5. Department of Interdisciplinary Oncology, The University of Arizona College of Medicine at Phoenix, Phoenix, AZ, USA

    Keping Xie

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Correspondence to Ming Quan, Jingde Chen or Keping Xie.

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Cui, J., Quan, M., Xie, D. et al. A novel KDM5A/MPC-1 signaling pathway promotes pancreatic cancer progression via redirecting mitochondrial pyruvate metabolism. Oncogene 39, 1140–1151 (2020). https://doi.org/10.1038/s41388-019-1051-8

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