m6A demethylase FTO stabilizes LINK-A to exert oncogenic roles via MCM3-mediated cell-cycle progression and HIF-1α activation

Yabing Nan; Shi Liu; Qingyu Luo; Xiaowei Wu; Pengfei Zhao; Wan Chang; Ruixiang Zhang; Yin Li; Zhihua Liu

doi:10.1016/j.celrep.2023.113273

m⁶A demethylase FTO stabilizes LINK-A to exert oncogenic roles via MCM3-mediated cell-cycle progression and HIF-1α activation

Cell Rep. 2023 Oct 31;42(10):113273. doi: 10.1016/j.celrep.2023.113273. Epub 2023 Oct 19.

Authors

Yabing Nan¹, Shi Liu¹, Qingyu Luo², Xiaowei Wu³, Pengfei Zhao¹, Wan Chang¹, Ruixiang Zhang⁴, Yin Li⁵, Zhihua Liu⁶

Affiliations

¹ State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
² Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
³ Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA.
⁴ Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
⁵ Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China. Electronic address: liyin@cicams.ac.cn.
⁶ State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China. Electronic address: liuzh@cicams.ac.cn.

PMID: 37858471
DOI: 10.1016/j.celrep.2023.113273

Abstract

RNA N⁶-methyladenosine (m⁶A) modification is implicated in cancer progression, yet its role in regulating long noncoding RNAs during cancer progression remains unclear. Here, we report that the m⁶A demethylase fat mass and obesity-associated protein (FTO) stabilizes long intergenic noncoding RNA for kinase activation (LINK-A) to promote cell proliferation and chemoresistance in esophageal squamous cell carcinoma (ESCC). Mechanistically, LINK-A promotes the interaction between minichromosome maintenance complex component 3 (MCM3) and cyclin-dependent kinase 1 (CDK1), increasing MCM3 phosphorylation. This phosphorylation facilitates the loading of the MCM complex onto chromatin, which promotes cell-cycle progression and subsequent cell proliferation. Moreover, LINK-A disrupts the interaction between MCM3 and hypoxia-inducible factor 1α (HIF-1α), abrogating MCM3-mediated HIF-1α transcriptional repression and promoting glycolysis and chemoresistance. These results elucidate the mechanism by which FTO-stabilized LINK-A plays oncogenic roles and identify the FTO/LINK-A/MCM3/HIF-1α axis as a promising therapeutic target for ESCC.

Keywords: CDK1; CP: Cancer; FTO; HIF-1α; LINK-A; MCM3; cell cycle progression; chemoresistance; esophageal squamous cell carcinoma; glycolysis; m(6)A.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alpha-Ketoglutarate-Dependent Dioxygenase FTO
Cell Line, Tumor
Cell Nucleus
Cell Proliferation
Esophageal Neoplasms*
Esophageal Squamous Cell Carcinoma*
Humans
Hypoxia-Inducible Factor 1, alpha Subunit
Minichromosome Maintenance Complex Component 3

Substances

Minichromosome Maintenance Complex Component 3
Hypoxia-Inducible Factor 1, alpha Subunit
MCM3 protein, human
FTO protein, human
Alpha-Ketoglutarate-Dependent Dioxygenase FTO