DNMT3a Promotes LUAD Cell Proliferation and Metastasis by Activating the HDAC7 Signalling Pathway

Overview

Journal Int J Biol Sci

Specialty Biology

Date 2025 Feb 24

PMID 39990668

Authors

Menglong Jiang

Xin Zhou

Yingtong Feng

Peng Ding

Jinfeng Li

Di Lu

Jiapei Qin

Yibing Bai

An Wang

Chunfang Xia

Jinliang Wang

Xiaolong Yan

Zhiqiang Ma

Renquan Zhang

Affiliations

Soon will be listed here.

Abstract

Changes in DNA methylation patterns, in which DNA methyltransferases such as DNA methyltransferase 3 alpha (DNMT3a) play important roles, are closely related to the occurrence and development of tumours. However, the role and mechanism of DNMT3a in lung adenocarcinoma (LUAD) remain unknown. The aim of this study was to investigate the potential effect of DNMT3a on LUAD cell proliferation and metastasis and explore the underlying molecular mechanism. Immunohistochemistry and Kaplan‒Meier survival analysis were used to investigate the relationship between the expression of DNMT3a and histone deacetylase 7 (HDAC7) and the survival, prognosis and clinicopathological features of patients. The effects of DNMT3a on the proliferation and metastasis of LUAD cells were studied and . Recombinant lentivirus-mediated gene overexpression or knockdown, western blotting, Quantitative real-time polymerase chain reaction (qRT‒PCR) and other methods were used in this study to elucidate the potential molecular mechanisms by which DNMT3a promotes LUAD cell proliferation and metastasis. High expression of DNMT3a or HDAC7 was positively correlated with poor prognosis, high AJCC 8th edition stage, and poor tumour differentiation in LUAD patients. LUAD patients with DNMT3a/HDAC7 co-low expression exhibited the worst prognosis. Upregulation of DNMT3a can promote LUAD cell proliferation and metastasis by upregulating HDAC7 and further activating the expression of downstream mediators ZEB1 and c-Myc. Conversely, overexpression of HDAC7 reversed the attenuation of tumour growth and metastasis and the suppression of c-Myc and ZEB1 expression mediated by downregulation of DNMT3a, further indicating the existence of positive feedback regulation between DNMT3a and HDAC7 in LUAD. Our findings first confirmed that DNMT3a acts as a tumour promoter inducing malignant progression of LUAD by upregulating HDAC7 and further inducing upregulation of ZEB1 and c-Myc. Targeting DNMT3a along with HDAC7 might be a promising therapeutic strategy for LUAD.

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