2. Academic Validation
  3. Numb/Parkin-directed mitochondrial fitness governs cancer cell fate via metabolic regulation of histone lactylation

Numb/Parkin-directed mitochondrial fitness governs cancer cell fate via metabolic regulation of histone lactylation

  • Cell Rep. 2023 Jan 30;42(2):112033. doi: 10.1016/j.celrep.2023.112033.
Yuman He 1,  Zhongzhong Ji 1,  Yiming Gong 1,  Liancheng Fan 1,  Penghui Xu 2,  Xinyu Chen 1,  Juju Miao 1,  Kai Zhang 1,  Wentian Zhang 3,  Pengfei Ma 1,  Huifang Zhao 1,  Chaping Cheng 1,  Deng Wang 2,  Jinming Wang 1,  Na Jing 4,  Kaiyuan Liu 1,  Pengcheng Zhang 5,  Baijun Dong 1,  Guanglei Zhuang 1,  Yujie Fu 6,  Wei Xue 1,  Wei-Qiang Gao 7,  Helen He Zhu 8
Affiliations

Affiliations

  • 1 State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Shanghai Cancer Institute & Department of Urology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, 160 Pujian Road, Shanghai 200127, China.
  • 2 School of Biomedical Engineering & Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, China.
  • 3 Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.
  • 4 State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Shanghai Cancer Institute & Department of Urology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, 160 Pujian Road, Shanghai 200127, China; School of Biomedical Engineering & Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, China.
  • 5 State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 6 Department of Thoracic Surgery, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 7 State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Shanghai Cancer Institute & Department of Urology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, 160 Pujian Road, Shanghai 200127, China; School of Biomedical Engineering & Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, China. Electronic address: gao.weiqiang@sjtu.edu.cn.
  • 8 State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Shanghai Cancer Institute & Department of Urology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, 160 Pujian Road, Shanghai 200127, China. Electronic address: zhuhecrane@shsmu.edu.cn.
PMID: 36724072 DOI: 10.1016/j.celrep.2023.112033
Abstract

Cell plasticity and neuroendocrine differentiation in prostate and lung adenocarcinomas are one of the major reasons for therapeutic resistance to targeted therapy. Whether and how metabolic changes contribute to this adenocarcinoma-to-neuroendocrine cell fate transition remains largely unclear. Here we show that neuroendocrine prostate or lung Cancer cells possess mostly fragmented mitochondria with low membrane potential and rely on glycolysis for energy metabolism. We further show an important role of the cell fate determinant Numb in mitochondrial quality control via binding to Parkin and facilitating Parkin-mediated Mitophagy. Deficiency in the Numb/Parkin pathway in prostate or lung adenocarcinomas causes a metabolic reprogramming featured with a significant increase in production of lactate acid, which subsequently leads to an upregulation of histone lactylation and transcription of neuroendocrine-associated genes. Collectively, the Numb/Parkin-directed mitochondrial fitness is a key metabolic switch and a promising therapeutic target on Cancer cell plasticity through the regulation of histone lactylation.

Keywords

CP: Cancer; CP: Metabolism; Numb; Parkin; cell fate plasticity; mitochondrial quality control; neuroendocrine differentiation; prostate cancer.

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