Glutamine signaling specifically activates c-Myc and Mcl-1 to facilitate cancer cell proliferation and survival.

Meng WANG; Fu-Shen GUO; Dai-Sen HOU; Hui-Lu ZHANG; Xiang-Tian CHEN; Yan-Xin SHEN; Zi-Fan GUO; Zhi-Fang ZHENG; Yu-Peng HU; Pei-Zhun DU; Chen-Ji WANG; Yan LIN; Yi-Yuan YUAN; Shi-Min ZHAO; Wei XU

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Glutamine signaling specifically activates c-Myc and Mcl-1 to facilitate cancer cell proliferation and survival.

Author: Meng WANG ¹ ; Fu-Shen GUO ¹ ; Dai-Sen HOU ¹ ; Hui-Lu ZHANG ² ; Xiang-Tian CHEN ¹ ; Yan-Xin SHEN ¹ ; Zi-Fan GUO ¹ ; Zhi-Fang ZHENG ³ ; Yu-Peng HU ¹ ; Pei-Zhun DU ² ; Chen-Ji WANG ¹ ; Yan LIN ¹ ; Yi-Yuan YUAN ¹ ; Shi-Min ZHAO ¹ ; Wei XU ¹
Author Information

1. Obstetrics & Gynecology Hospital of Fudan University, State Key Laboratory of Genetic and Development of Complex Phenotypes, Institutes of Biomedical Sciences, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases and Shanghai Key Laboratory of Metabolic Remodeling, Fudan University, Shanghai 200438, China.
2. Huashan Hospital, Fudan University, Shanghai 200040, China.
3. NHC Key Laboratory of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai 200032, China.
Publication Type:Journal Article
Keywords: FBW7; Mcl-1; QARS; c-Myc; glutamine; glutamylation
MeSH: Glutamine/metabolism*; Myeloid Cell Leukemia Sequence 1 Protein/genetics*; Humans; Proto-Oncogene Proteins c-myc/genetics*; Cell Proliferation; Signal Transduction; Neoplasms/pathology*; F-Box-WD Repeat-Containing Protein 7/genetics*; Cell Survival; Cell Line, Tumor; Apoptosis
From: Protein & Cell 2025;16(11):968-984
CountryChina
Language:English
Abstract: Glutamine provides carbon and nitrogen to support the proliferation of cancer cells. However, the precise reason why cancer cells are particularly dependent on glutamine remains unclear. In this study, we report that glutamine modulates the tumor suppressor F-box and WD repeat domain-containing 7 (FBW7) to promote cancer cell proliferation and survival. Specifically, lysine 604 (K604) in the sixth of the 7 substrate-recruiting WD repeats of FBW7 undergoes glutaminylation (Gln-K604) by glutaminyl tRNA synthetase. Gln-K604 inhibits SCFFBW7-mediated degradation of c-Myc and Mcl-1, enhances glutamine utilization, and stimulates nucleotide and DNA biosynthesis through the activation of c-Myc. Additionally, Gln-K604 promotes resistance to apoptosis by activating Mcl-1. In contrast, SIRT1 deglutaminylates Gln-K604, thereby reversing its effects. Cancer cells lacking Gln-K604 exhibit overexpression of c-Myc and Mcl-1 and display resistance to chemotherapy-induced apoptosis. Silencing both c-MYC and MCL-1 in these cells sensitizes them to chemotherapy. These findings indicate that the glutamine-mediated signal via Gln-K604 is a key driver of cancer progression and suggest potential strategies for targeted cancer therapies based on varying Gln-K604 status.