SIRT7 promotes mitochondrial biogenesis to render the adaptive resistance to MAPK inhibition in melanoma

Du, Juan1; Yi, Xiuli1; Guo, Sen1; Wang, Huina1; Shi, Qiong1; Zhang, Jianglin2,3; Tian, Yangzi1; Wang, Hao1; Zhang, Hengxiang1; Zhang, Baolu1; Gao, Tianwen1; Li, Chunying1; Guo, Weinan1; Yang, Yuqi1

2024-08-30

10.1016/j.bbrc.2024.150161

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   影响因子和分区

0006-291X

1090-2104

Melanoma, arising from the malignant transformation of melanocytes, stands as the most lethal type of skin cancer. While significant strides have been made in targeted therapy and immunotherapy, substantially enhancing therapeutic efficacy, the prognosis for melanoma patients remains unoptimistic. SIRT7, a nuclearlocalized deacetylase, plays a pivotal role in maintaining cellular homeostasis and adapting to external stressors in melanoma, with its activity closely tied to intracellular nicotinamide adenine dinucleotide (NAD+). However, its involvement in adaptive resistance to targeted therapy remains unclear. Herein, we unveil that upregulated SIRT7 promotes mitochondrial biogenesis to render the adaptive resistance to MAPK inhibition in melanoma. Initially, we observed a significant increase of SIRT7 expression in publicly available datasets following targeted therapy within a short duration. In consistent, we found elevated SIRT7 expression in melanoma cells subjected to BRAF or MEK inhibitors in vitro. The up -regulation of SIRT7 expression was also confirmed in xenograft tumors in mice after targeted therapy in vivo. Furthermore, we proved that SIRT7 deficiency led to decreased cell viability upon prolonged exposure to BRAF or MEK inhibitors, accompanied by an increase in cell apoptosis. Mechanistically, SIRT7 deficiency restrained the upregulation of genes associated with mitochondrial biogenesis and intracellular ATP levels in response to targeted therapy treatment in melanoma cells. Ultimately, we proved that SIRT7 deficieny could sensitize BRAF-mutant melanoma cells to MAPK inhibition targeted therapy in vivo. In conclusion, our findings underscore the role of SIRT7 in fostering adaptive resistance to targeted therapy through the facilitation of mitochondrial biogenesis. Targeting SIRT7 emerges as a promising strategy to overcome MAPK inhibitor adaptive resistance in melanoma.

SIRT7 Melanoma MAPK inhibition adaptive resistance Mitochondrial biogenesis

SCI

英语

其他

National Natural Science Foundation of China["82273182","82273101","82273503"] ; Young Eagle Project of Fourth Military Medical University[2019cyjhgwn]

Biochemistry & Molecular Biology ; Biophysics

Biochemistry & Molecular Biology ; Biophysics

WOS:001246281800001

ACADEMIC PRESS INC ELSEVIER SCIENCE

BIOLOGY & BIOCHEMISTRY

Web of Science

1.Fourth Mil Med Univ, Xijing Hosp, Dept Dermatol, Xian, Shaanxi, Peoples R China
2.Southern Univ Sci & Technol, Jinan Univ, Shenzhen Peoples Hosp, Affiliated Hosp 1,Clin Med Coll 2,Dept Dermatol, Shenzhen, Guangdong, Peoples R China
3.Natl Clin Res Ctr Skin Dis, Candidate Branch, Shenzhen, Guangdong, Peoples R China

Du, Juan,Yi, Xiuli,Guo, Sen,et al. SIRT7 promotes mitochondrial biogenesis to render the adaptive resistance to MAPK inhibition in melanoma[J]. BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS,2024,722.

Du, Juan.,Yi, Xiuli.,Guo, Sen.,Wang, Huina.,Shi, Qiong.,...&Yang, Yuqi.(2024).SIRT7 promotes mitochondrial biogenesis to render the adaptive resistance to MAPK inhibition in melanoma.BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS,722.

Du, Juan,et al."SIRT7 promotes mitochondrial biogenesis to render the adaptive resistance to MAPK inhibition in melanoma".BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 722(2024).