Open AccessMethyltransferase SETD2 inhibits tumor growth and metastasis via STAT1–IL‐8 signaling‐mediated epithelial–mesenchymal transition in lung adenocarcinoma
Author(s) -
Yang Xin,
Chen Rui,
Chen Yan,
Zhou You,
Wu Chen,
Li Qing,
Wu Jun,
Hu Wenwei,
Zhao Weiqing,
Wei Wei,
Shi Juntao,
Ji Mei
Publication year - 2022
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.15299
Subject(s) - carcinogenesis , cancer research , epithelial–mesenchymal transition , biology , gene knockdown , adenocarcinoma , lung cancer , tumor progression , metastasis , methyltransferase , cancer , pathology , medicine , cell culture , methylation , gene , genetics
Lung adenocarcinoma (LUAD) is a major subtype of non–small‐cell lung cancer, which is the leading cause of cancer death worldwide. The histone H3K36 methyltransferase SETD2 has been reported to be frequently mutated or deleted in types of human cancer. However, the functions of SETD2 in tumor growth and metastasis in LUAD has not been well illustrated. Here, we found that SETD2 was significantly downregulated in human lung cancer and greatly impaired proliferation, migration, and invasion in vitro and in vivo . Furthermore, we found that SETD2 overexpression significantly attenuated the epithelial–mesenchymal transition (EMT) of LUAD cells. RNA‐seq analysis identified differentially expressed transcripts that showed an elevated level of interleukin 8 (IL‐8) in STED2‐knockdown LUAD cells, which was further verified using qPCR, western blot, and promoter luciferase report assay. Mechanically, SETD2‐mediated H3K36me3 prevented assembly of Stat1 on the IL‐8 promoter and contributed to the inhibition of tumorigenesis in LUAD. Our findings highlight the suppressive role of SETD2/H3K36me3 in cell proliferation, migration, invasion, and EMT during LUAD carcinogenesis, via regulation of the STAT1–IL‐8 signaling pathway. Therefore, our studies on the molecular mechanism of SETD2 will advance our understanding of epigenetic dysregulation at LUAD progression.