Acetylated STAT3-induced DIRAS2 deletion promotes the proliferation of triple-negative breast cancer cells

Lifen Zhang; Lu Wang; Lin Zhao; Minna Luo; Shan Shao; Shanzhi GU

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Acetylated STAT3-induced DIRAS2 deletion promotes the proliferation of triple-negative breast cancer cells

VernacularTitle:乙酰化STAT3诱导的DIRAS2缺失促进三阴性乳腺癌细胞的增殖
Author: Lifen ZHANG ¹ ; Lu WANG ¹ ; Lin ZHAO ¹ ; Minna LUO ² ; Shan SHAO ¹ ; Shanzhi GU ³
Author Information

1. Department of Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061
2. Department of Hematology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061
3. Department of Forensic Medicine, Xi’an Jiaotong University, Xi’an 710061, China
Publication Type:Journal Article
Keywords: triple-negative breast cancer (TNBC); Ac-STAT3; DIRAS2; methylation; proliferation
From: Journal of Xi'an Jiaotong University(Medical Sciences) 2024;45(5):741-747
CountryChina
Language:Chinese
Abstract: 【Objective】 To explore the regulation of DIRAS2 gene expression by acetylated STAT3 and its involvement in the proliferation of triple-negative breast cancer (TNBC) cells. 【Methods】 The expression levels of DIRAS2 and acetylated STAT3 in TNBC tissues and cells were analyzed by database query, Western blotting, and qRT-PCR. TNBC cell lines MDA-MB-231 and SUM159 were selected, and lentivirus or plasmid was used to construct DIRAS2 overexpression and STAT3 wild or Lys685 mutation cell lines. The CCK-8 assay was used to evaluate the effect of DIRAS2 and STAT3 acetylation on the proliferation of TNBC cells. Western blotting, pyrosequencing, ChIP and IP were employed to investigate the regulatory effect and mechanism of acetylated STAT3 on DIRAS2 expression. 【Results】 The expression of DIRAS2 was decreased in TNBC tissues and cells. Pyrosequencing analysis found that the methylation level of CpG islands in the DIRAS2 promoter was increased in TNBC cells compared with normal breast epithelial cells, which promoted the growth of cancer cells. Furthermore, TNBC cells showed an increase in STAT3 acetylation, which was accompanied by a shift in the methylation status of the DIRAS2 promoter. ChIP and IP experiments showed that acetylated STAT3 could bind to the DIRAS2 promoter, and the STAT3 Lys685 mutation disrupted the interaction between STAT3 and DNMT1. 【Conclusion】 Acetylated STAT3 induces DIRAS2 promoter methylation by recruiting DNMT1, leading to loss of DIRAS2 expression and cancer cell proliferation in TNBC.