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Journal of Experimental & Clinical Cancer Research

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01-12-2021 | NSCLC | Research

An SETD1A/Wnt/β-catenin feedback loop promotes NSCLC development

Authors: Rui Wang, Jian Liu, Kai Li, Ganghua Yang, Sisi Chen, Jie Wu, Xinming Xie, Hong Ren, Yamei Pang

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2021

Abstract

Background

SETD1A, a member of SET1/MLL family H3K4 methyltransferases, is involved in the tumorigenesis of numerous cancers. However, the biological role and mechanism of SETD1A in non-small cell lung cancer (NSCLC) remain to be elucidated.

Methods

The expression of SETD1A, NEAT1, EZH2, and β-catenin in NSCLC tissues and cell lines was detected by qRT-PCR, immunohistochemistry and western blotting. The regulatory mechanisms were validated by chromatin immunoprecipitation, co-immunoprepitation and luciferase reporter assay. The self-renewal, cisplatin sensitivity and tumorigenesis of NSCLC cells were analyzed using sphere formation, CCK-8, colony formation assays and xenograft tumor models.

Results

SETD1A expression was significantly increased in NSCLC and its overexpression predicted a poor prognosis of patients with NSCLC. Functional experiments showed that SETD1A positively regulated cancer stem cell property and negatively regulated cisplatin sensitivity in NSCLC cells via the Wnt/β-catenin pathway. Next, we found that SETD1A positively regulated the Wnt/β-catenin pathway via interacting with and stabilizing β-catenin. The SET domain is dispensable for the interaction between SETD1A and β-catenin. Furthermore, we identified that SETD1A bound to the promoters of NEAT1 and EZH2 to activate gene transcription by inducing H3K4me3 enrichment. Rescue experiments showed that SETD1A promoted the Wnt/β-catenin pathway and exerted its oncogenic functions in NSCLC, at least, partly through NEAT1 and EZH2 upregulation. In addition, SETD1A was proven to be a direct target of the Wnt/β-catenin pathway, thus forming a positive feedback loop in NSCLC cells.

Conclusion

SETD1A and Wnt/β-catenin pathway form a positive feedback loop and coordinately contribute to NSCLC progression.

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Title: An SETD1A/Wnt/β-catenin feedback loop promotes NSCLC development
Authors: Rui Wang
Jian Liu
Kai Li
Ganghua Yang
Sisi Chen
Jie Wu
Xinming Xie
Hong Ren
Yamei Pang
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: NSCLC
NSCLC
Published in: Journal of Experimental & Clinical Cancer Research / Issue 1/2021
Electronic ISSN: 1756-9966
DOI: https://doi.org/10.1186/s13046-021-02119-x

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