PER3启动子高甲基化与多癌症的进展相关
PER3 promoter hypermethylation correlates to the progression of pan-cancer
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影响因子:4.4
分区:医学2区 / 遗传学2区 肿瘤学2区
发表日期:2024 Oct 14
作者:
Yaoxu Li, Wenjuan Li, Jinhai Deng, Mingzhu Yin
DOI:
10.1186/s13148-024-01760-5
摘要
恶性肿瘤细胞中的期节律调节蛋白3（PER3）表达降低。然而，PER3在癌症中的表达变化机制及其在肿瘤进展中的具体作用尚不清楚。我们利用多个公共数据库，进行生物信息学分析，并通过体外和体内实验验证。发现大多数癌症中PER3表达下降，PER3下调与多种癌症的预后不良相关。PER3启动子甲基化水平在11种癌症中升高，其中在乳腺浸润性癌、结肠腺癌、头颈鳞癌、肾乳头状细胞癌（KIRP）、肺腺癌（LUAD）和子宫体内膜癌中，CGI岛（cg12258811和cg14204433）甲基化与PER3表达呈负相关。cg12258811的高甲基化与患者生存期缩短及癌症晚期相关，硫酸氢甲基化测序证实了该位点的甲基化增强与PER3表达降低的关系。体外和体内实验表明，PER3抑制KIRP和LUAD的进展，去甲基化药物Decitabine通过降低启动子（cg12258811）甲基化水平，增强PER3表达，抑制肿瘤细胞功能。本研究深化了对PER3在癌症中表达变化机制的理解，确认了PER3高甲基化和表达下调的肿瘤相关功能。
Abstract
Malignant cells exhibit reduced period circadian regulator 3 (PER3) expression. However, the underlying mechanisms of variations in PER3 expression in cancers and the specific function of PER3 in tumor progression remain poorly understood.We explored multiple public databases, conducted bioinformatics analyses, and performed in vitro and in vivo experiments for validation. We found PER3 expression was decreased in most types of cancers, and PER3 downregulation was associated with a poor prognosis in 8 types of cancer. PER3 promoter methylation levels were increased in 11 types of cancer. Promoter hypermethylation (CpG islands [CGIs] cg12258811 and cg14204433) correlated with decreased PER3 expression in six cancers (breast invasive carcinoma, colon adenocarcinoma, head and neck squamous cell carcinoma, kidney renal papillary cell carcinoma [KIRP], lung adenocarcinoma [LUAD], and uterine corpus endometrial carcinoma). CGI cg12258811 hypermethylation was associated with reduced survival time and advanced cancer stages. Moreover, the bisulfite pyrosequencing assay confirmed CGI cg12258811 hypermethylation and its negative correlation with PER3 expression. In vitro and in vivo experiments demonstrated that PER3 inhibited KIRP and LUAD progression. Decitabine enhanced PER3 expression and inhibited KIRP cell functions by reducing promoter (cg12258811) methylation level.Our findings advanced the mechanistic understanding of variations in PER3 expression in cancers and confirmed the tumor-associated function of PER3 hypermethylation and downregulation.