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

被引：90

作者：

He, Yuman ^{[1
,2
]}

Ji, Zhongzhong ^{[1
,2
]}

Gong, Yiming ^{[1
,2
]}

Fan, Liancheng ^{[1
,2
]}

Xu, Penghui ^{[3
,4
]}

Chen, Xinyu ^{[1
,2
]}

Miao, Juju ^{[1
,2
]}

Zhang, Kai ^{[1
,2
]}

Zhang, Wentian ^{[5
]}

Ma, Pengfei ^{[1
,2
]}

Zhao, Huifang ^{[1
,2
]}

Cheng, Chaping ^{[1
,2
]}

Wang, Deng ^{[3
,4
]}

Wang, Jinming ^{[1
,2
]}

Jing, Na ^{[1
,2
,3
,4
]}

Liu, Kaiyuan ^{[1
,2
]}

Zhang, Pengcheng ^{[6
,7
]}

Dong, Baijun ^{[1
,2
]}

Zhuang, Guanglei ^{[1
,2
]}

Fu, Yujie ^{[8
]}

Xue, Wei ^{[1
,2
]}

Gao, Wei-Qiang ^{[1
,2
,3
,4
]}

Zhu, Helen He ^{[1
,2
]}

机构：

[1] Shanghai Jiao Tong Univ, Sch Med, Renji Medx Stem Cell Res Ctr, State Key Lab Oncogenes & Related Genes,Shanghai C, 160 Pujian Rd, Shanghai 200127, Peoples R China

[2] Shanghai Jiao Tong Univ, Sch Med, Ren Ji Hosp, Dept Urol, 160 Pujian Rd, Shanghai 200127, Peoples R China

[3] Shanghai Jiao Tong Univ, Sch Biomed Engn, Shanghai 200030, Peoples R China

[4] Shanghai Jiao Tong Univ, MedX Res Inst, Shanghai 200030, Peoples R China

[5] Tongji Univ, Sch Med, Shanghai Pulm Hosp, Dept Thorac Surg, Shanghai 200433, Peoples R China

[6] Chinese Acad Sci, State Key Lab Drug Res, Shanghai 201203, Peoples R China

[7] Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Pharmaceut, Shanghai 201203, Peoples R China

[8] Shanghai Jiao Tong Univ, Sch Med, Ren Ji Hosp, Dept Thorac Surg, Shanghai, Peoples R China

来源：

CELL REPORTS | 2023年 / 42卷 / 02期

基金：

国家重点研发计划; 中国国家自然科学基金;

关键词：

PROSTATE-CANCER; LINEAGE PLASTICITY; MAMMALIAN NUMB; LUNG-CANCER; PARKIN; PINK1; UBIQUITIN; EXPRESSION; SUBPOPULATION; LOCALIZATION;

D O I：

10.1016/j.celrep.2023.112033

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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 mi-tophagy. 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.

引用

页数：26

共 61 条

[21] Mitochondrial dynamics in postmitotic cells regulate neurogenesis [J].