FTO regulates the chemo‐radiotherapy resistance of cervical squamous cell carcinoma (CSCC) by targeting β‐catenin through mRNA demethylation

• Published in: Molecular carcinogenesis Vol. 57; no. 5; pp. 590 - 597
• Main Authors: Zhou, Shun, Bai, Zhou‐Lan, Xia, Di, Zhao, Zhi‐Jun, Zhao, Ren, Wang, Yan‐Yang, Zhe, Hong
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.05.2018
• Subjects: Adenosine - analogs & derivatives; Adenosine - metabolism; Alpha-Ketoglutarate-Dependent Dioxygenase FTO - genetics; Animals; beta Catenin - genetics; Body fat; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; Catenin; Cell Line, Tumor; Cervical cancer; cervical squamous cell carcinoma; Cervix; Chemoradiotherapy; chemo‐radiotherapy resistance; Demethylation; DNA-Binding Proteins - metabolism; Drug Resistance, Neoplasm; Endonucleases - metabolism; ERCC1 protein; Female; FTO; Humans; m6A; Mice; N6-methyladenosine; Neoplasm Transplantation; Prognosis; Radiation therapy; Radiation Tolerance; Squamous cell carcinoma; Survival Analysis; Up-Regulation; Uterine Cervical Neoplasms - genetics; Uterine Cervical Neoplasms - metabolism; Uterine Cervical Neoplasms - pathology; FTO; m6A; cervical squamous cell carcinoma; chemo-radiotherapy resistance
• ISSN: 0899-1987; 1098-2744; 1098-2744
• DOI: 10.1002/mc.22782

The role of N6‐methyladenosine (m6A) demethylase fat mass and obesity‐associated protein (FTO) in the regulation of chemo‐radiotherapy resistance remains largely unknown. Here, we show that the mRNA level of FTO is elevated in cervical squamous cell carcinoma (CSCC) tissues when compared with respective adjacent normal tissues. FTO enhances the chemo‐radiotherapy resistance both in vitro and in vivo through regulating expression of β‐catenin by reducing m6A levels in its mRNA transcripts and in turn increases excision repair cross‐complementation group 1 (ERCC1) activity. Clinically, the prognostic value of FTO for overall survival is found to be dependent on β‐catenin expression in human CSCC samples. Taken together, these findings uncover a critical function for FTO and its substrate m6A in the regulation of chemo‐radiotherapy resistance, which may bear potential clinical implications for CSCC treatment.