FTO promotes cervical cancer cell proliferation, colony formation, migration and invasion via the regulation of the BMP4/Hippo/YAP1/TAZ pathway

Jinyuan Huang; Jing Yang; Yudi Zhang; Dan Lu; Yinmei Dai

doi:10.1016/j.yexcr.2023.113585

FTO promotes cervical cancer cell proliferation, colony formation, migration and invasion via the regulation of the BMP4/Hippo/YAP1/TAZ pathway

Exp Cell Res. 2023 Jun 1;427(1):113585. doi: 10.1016/j.yexcr.2023.113585. Epub 2023 Apr 6.

Authors

Jinyuan Huang¹, Jing Yang¹, Yudi Zhang¹, Dan Lu¹, Yinmei Dai²

Affiliations

¹ Department of Gynecology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University/Beijing Maternal and Child Health Care Hospital, Beijing, China.
² Department of Gynecology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University/Beijing Maternal and Child Health Care Hospital, Beijing, China. Electronic address: fcyydym@ccmu.edu.cn.

PMID: 37030332
DOI: 10.1016/j.yexcr.2023.113585

Abstract

Cervical cancer is the fourth most common malignancy tumor worldwide with high incidence and mortality. Accumulating evidence indicated that through an m⁶A-dependent or m⁶A-independent mechanism, fat mass and obesity associated gene (FTO) exhibits the tumor-promoting and suppressive roles of FTO involved in various cancers, including cervical cancer. This study aims to verify the biological function and potential mechanisms of FTO in cervical cancer cell proliferation, colony formation, migration, and invasion in vitro as well as tumor growth in vivo. Herein, we confirmed that knockdown of FTO inhibits cell proliferation, colony formation, migration, and invasion of cervical cancer cells in vitro via cell counting kit-8 (CCK8) assay, colony formation assay, and transwell migration and invasion assay. The demethylase activity of FTO is required for cell proliferation, colony formation, migration, and invasion of cervical cancer cells in vitro. RNA sequencing, online database analysis, and western blotting revealed that FTO regulated the BMP4/Hippo/YAP1/TAZ pathway. In addition, FTO upregulates the expression of BMP4 in an m⁶A-dependent manner and binds to the N-terminal of BMP4 to form a dimer at the C-terminal in cervical cancer cells through protein-protein interaction. We further discovered that BMP4 treatment promoted cell proliferation, colony formation, migration, and invasion of cervical cancer cells, and rescue experiments validated that BMP4 treatment reversed the inhibition of FTO knockdown on the Hippo/YAP1/TAZ pathway and the progression of cervical cancer cells in vitro. Notably, the knockdown of FTO significantly suppressed xenograft tumor growth and the protein level of BMP4 in vivo. Collectively, our results demonstrate that the FTO promotes cervical cancer progression in vitro and in vivo via the regulation of the BMP4/Hippo/YAP1/TAZ pathway, suggesting that FTO acts as an oncogenic molecule and the FTO/BMP4 Hippo/YAP1/TAZ axis may serve as valuable targets for cervical cancer treatment.

Keywords: BMP4; Cervical cancer; FTO; Hippo/YAP1/TAZ pathway; m6A-dependent manner.

MeSH terms

Alpha-Ketoglutarate-Dependent Dioxygenase FTO / genetics
Bone Morphogenetic Protein 4 / genetics
Cell Line, Tumor
Cell Proliferation / genetics
Female
Gene Expression Regulation, Neoplastic
Hippo Signaling Pathway
Humans
Uterine Cervical Neoplasms* / genetics
Uterine Cervical Neoplasms* / pathology

Substances

Alpha-Ketoglutarate-Dependent Dioxygenase FTO
BMP4 protein, human
Bone Morphogenetic Protein 4
FTO protein, human