NNMT-DNMT1 Axis is Essential for Maintaining Cancer Cell Sensitivity to Oxidative Phosphorylation Inhibition

Changqing Wu; Yu'e Liu; Wenju Liu; Tianhui Zou; Shaojuan Lu; Chengjie Zhu; Le He; Jie Chen; Lan Fang; Lin Zou; Ping Wang; Lihong Fan; Hongxiang Wang; Han You; Juxiang Chen; Jing-Yuan Fang; Cizhong Jiang; Yufeng Shi

doi:10.1002/advs.202202642

NNMT-DNMT1 Axis is Essential for Maintaining Cancer Cell Sensitivity to Oxidative Phosphorylation Inhibition

Adv Sci (Weinh). 2022 Nov 16;10(1):e2202642. doi: 10.1002/advs.202202642. Online ahead of print.

Authors

Changqing Wu¹, Yu'e Liu¹, Wenju Liu², Tianhui Zou³, Shaojuan Lu¹, Chengjie Zhu¹, Le He¹, Jie Chen¹, Lan Fang¹, Lin Zou⁴, Ping Wang¹, Lihong Fan⁵, Hongxiang Wang⁶, Han You⁷, Juxiang Chen⁶, Jing-Yuan Fang³, Cizhong Jiang², Yufeng Shi^{1

2

8}

Affiliations

¹ Tongji University Cancer Center, Shanghai Tenth People's Hospital of Tongji University, School of Medicine, Tongji University, Shanghai, 200092, China.
² Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
³ State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
⁴ Clinical Research Unit, Children's Hospital of Shanghai Jiaotong University, Shanghai, 200062, China.
⁵ Department of Respiratory Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China.
⁶ Department of Neurosurgery, Changhai Hospital, Naval Medical University, NO.168 Changhai Road, Shanghai, 200433, China.
⁷ State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, 361005, China.
⁸ Clinical Center for Brain and Spinal Cord Research, Tongji University, Shanghai, 200092, China.

Abstract

Lacking a clear understanding of the molecular mechanism determining cancer cell sensitivity to oxidative phosphorylation (OXPHOS) inhibition limits the development of OXPHOS-targeting cancer treatment. Here, cancer cell lines sensitive or resistant to OXPHOS inhibition are identified by screening. OXPHOS inhibition-sensitive cancer cells possess increased OXPHOS activity and silenced nicotinamide N-methyltransferase (NNMT) expression. NNMT expression negatively correlates with OXPHOS inhibition sensitivity and functionally downregulates the intracellular levels of S-adenosyl methionine (SAM). Expression of DNA methyltransferase 1 (DNMT1), a SAM consumer, positively correlates with OXPHOS inhibition sensitivity. NNMT overexpression and DNMT1 inhibition render OXPHOS inhibition-sensitive cancer cells resistant. Importantly, treatments of OXPHOS inhibitors (Gboxin and Berberine) hamper the growth of mouse tumor xenografts by OXPHOS inhibition sensitive but not resistant cancer cells. What's more, the retrospective study of 62 tumor samples from a clinical trial demonstrates that administration of Berberine reduces the tumor recurrence rate of NNMT^low /DNMT1^high but not NNMT^high /DNMT1^low colorectal adenomas (CRAs). These results thus reveal a critical role of the NNMT-DNMT1 axis in determining cancer cell reliance on mitochondrial OXPHOS and suggest that NNMT and DNMT1 are faithful biomarkers for OXPHOS-targeting cancer therapies.

Keywords: DNA methylation; N-methyltransferase (NNMT); S-adenosyl methionine (SAM); biomarker; cancer; oxidative phosphorylation (OXPHOS).

Abstract

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