YTHDC1-dependent m6A modification modulated FOXM1 promotes glycolysis and tumor progression through CENPA in triple-negative breast cancer

作者全名："Shen, Xi; Zhong, Jianxin; Yu, Pan; Liu, Feng; Peng, Haoran; Chen, Nianyong"

作者地址："[Shen, Xi] Sun Yat Sen Univ, Affiliated Hosp 8, Dept Oncol, Shenzhen, Peoples R China; [Chen, Nianyong] Sichuan Univ, West China Hosp, Canc Ctr, Dept Radiat Oncol, Chengdu, Peoples R China; [Chen, Nianyong] Sichuan Univ, West China Hosp, Canc Ctr, Div Head & Neck Tumor Multimodal Treatment, Chengdu, Peoples R China; [Zhong, Jianxin] Peking Univ, Canc Hosp & Inst, Minist Educ, Key Lab Carcinogenesis & Translat Res,Dept Breast, Beijing, Peoples R China; [Yu, Pan] Chongqing Med Univ, Hosp 2, Dept Hlth Management, Chongqing, Peoples R China; [Liu, Feng] Wuhan Fourth Hosp, Dept Thyroid & Breast Surg, Wuhan, Peoples R China; [Peng, Haoran] Univ Chinese Acad Sci, Shenzhen Hosp, Dept Stomatol, Shenzhen, Peoples R China; [Chen, Nianyong] Sichuan Univ, West China Hosp, Dept Head & Neck Oncol, Chengdu 610041, Sichuan, Peoples R China; [Chen, Nianyong] Sichuan Univ, West China Hosp, Canc Ctr, Dept Radiat Oncol, Chengdu 610041, Sichuan, Peoples R China"

通信作者："Chen, NY (通讯作者)，Sichuan Univ, West China Hosp, Dept Head & Neck Oncol, Chengdu 610041, Sichuan, Peoples R China.; Chen, NY (通讯作者)，Sichuan Univ, West China Hosp, Canc Ctr, Dept Radiat Oncol, Chengdu 610041, Sichuan, Peoples R China."

来源：CANCER SCIENCE

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001195630200001

JCR分区：Q1

影响因子：5.7

年份：2024

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期号：　

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文献类型：Article; Early Access

关键词：CENPA; FOXM1 transcription factor; glycolysis; TNBC; YTHDC1-dependent m6A modification

摘要："Triple-negative breast cancer (TNBC) exhibits heightened aggressiveness compared with other breast cancer (BC) subtypes, with earlier relapse, a higher risk of distant metastasis, and a worse prognosis. Transcription factors play a pivotal role in various cancers. Here, we found that factor forkhead box M1 (FOXM1) expression was significantly higher in TNBC than in other BC subtypes and normal tissues. Combining the findings of Gene Ontology (GO) enrichment analysis and a series of experiments, we found that knockdown of the FOXM1 gene attenuated the ability of TNBC cells to proliferate and metastasize both in vivo and in vitro. In addition, Spearman's test showed that FOXM1 significantly correlated with glycolysis-related genes, especially centromere protein A (CENPA) in datasets (GSE76250, GSE76124, GSE206912, and GSE103091). The effect of silencing FOXM1 on the inhibition of CENPA expression, TNBC proliferation, migration, and glycolysis could be recovered by overexpression of CENPA. According to MeRIP, the level of m6A modification on FOMX1 decreased in cells treated with cycloleucine (a m6A inhibitor) compared with that in the control group. The increase in FOXM1 expression caused by YTHDC1 overexpression could be reversed by the m6A inhibitor, which indicated that YTHDC1 enhanced FOXM1 expression depending on m6A modification. Therefore, we concluded that the YTHDC1-m6A modification/FOXM1/CENPA axis plays an important role in TNBC progression and glycolysis. Using bioinformatics and in vivo and in vitro experiments, we identified that the YTHDC1-dependent m6A/FOXM1/CENPA axis is involved in the regulation of glycolysis and the progression of TNBC. This discovery provides new insight into the molecular interactions driving TNBC and potential therapeutic targets for combating this aggressive cancer.image"

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