Department of Stomatology, Chongqing University Three Gorges Hospital, School of Medicine, Chongqing University, Wanzhou District, Chongqing, 404100, China.
Clinical Research Center (CRC), Medical Pathology Center (MPC), Cancer Early Detection and Treatment Center (CEDTC) and Translational Medicine Research Center (TMRC), Chongqing University Three Gorges Hospital, School of Medicine, Chongqing University, Wanzhou District, Chongqing, 404100, China.
Clin Epigenetics. 2024 Oct 14;16(1):140. doi: 10.1186/s13148-024-01760-5.
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.
恶性细胞表现出周期节律调节因子 3（PER3）表达减少。然而，癌症中 PER3 表达变化的潜在机制以及 PER3 在肿瘤进展中的具体功能仍知之甚少。
我们探索了多个公共数据库，进行了生物信息学分析，并进行了体外和体内实验验证。我们发现 PER3 表达在大多数类型的癌症中降低，PER3 下调与 8 种癌症的不良预后相关。PER3 启动子甲基化水平在 11 种癌症中增加。启动子超甲基化（CpG 岛 cg12258811 和 cg14204433）与六种癌症（乳腺浸润性导管癌、结肠腺癌、头颈部鳞状细胞癌、肾乳头状肾细胞癌[KIRP]、肺腺癌[LUAD]和子宫体子宫内膜癌）中的 PER3 表达降低相关。CGI cg12258811 超甲基化与生存时间缩短和癌症晚期相关。此外，亚硫酸氢盐焦磷酸测序验证了 CGI cg12258811 超甲基化及其与 PER3 表达的负相关。体外和体内实验表明 PER3 抑制了 KIRP 和 LUAD 的进展。地西他滨通过降低启动子（cg12258811）甲基化水平来增强 PER3 表达并抑制 KIRP 细胞功能。
我们的研究结果推进了对癌症中 PER3 表达变化的机制理解，并证实了 PER3 甲基化和下调与肿瘤相关的功能。
