Cellular senescence gene TACC3 associated with colorectal cancer risk via genetic and DNA methylated alteration

• Published in: Archives of toxicology Vol. 98; no. 5; pp. 1499 - 1513
• Main Authors: Shen, Hengyang, Chen, Yang, Xu, Menghuan, Zhou, Jieyu, Huang, Changzhi, Wang, Zhenling, Shao, Yu, Zhang, Hongqiang, Lu, Yunfei, Li, Shuwei, Fu, Zan
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.05.2024; Springer Nature B.V
• Subjects: Azacytidine; Biomedical and Life Sciences; Biomedicine; Cancer; Cell Cycle Proteins - genetics; Cell proliferation; cell senescence; Cellular Senescence - genetics; Colorectal cancer; Colorectal carcinoma; colorectal neoplasms; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Correlation analysis; CpG Islands; Deoxyribonucleic acid; DNA; DNA Methylation; Environmental Health; Epigenesis, Genetic; Epigenetics; Gene expression; Gene Expression Regulation, Neoplastic; Genes; Genetic analysis; Genetic diversity; Genetic variance; Genomes; Genotoxicity and Carcinogenicity; Health risks; Humans; immunosuppression; Microenvironments; Microtubule-Associated Proteins - genetics; Occupational Medicine/Industrial Medicine; Pathogenesis; Pharmacology/Toxicology; Phenotypes; Phenotypic variations; promoter regions; Regulatory mechanisms (biology); Risk; Senescence; sequence analysis; Support vector machines; Tumor Microenvironment; DNA methylation; Senescence; Susceptibility; Colorectal cancer; TACC3
• ISSN: 0340-5761; 1432-0738; 1432-0738
• DOI: 10.1007/s00204-024-03702-9

Cell senescence genes play a vital role in the pathogenesis of colorectal cancer, a process that may involve the triggering of genetic variations and reversible phenotypes caused by epigenetic modifications. However, the specific regulatory mechanisms remain unclear. Using CellAge and The Cancer Genome Atlas databases and in-house RNA-seq data, DNA methylation-modified cellular senescence genes (DMCSGs) were validated by Support Vector Machine and correlation analyses. In 1150 cases and 1342 controls, we identified colorectal cancer risk variants in DMCSGs. The regulatory effects of gene, variant, and DNA methylation were explored through dual-luciferase and 5-azacytidine treatment experiments, complemented by multiple database analyses. Biological functions of key gene were evaluated via cell proliferation assays, SA-β-gal staining, senescence marker detection, and immune infiltration analyses. The genetic variant rs4558926 in the downstream of TACC3 was significantly associated with colorectal cancer risk (OR = 1.35, P  = 3.22 × 10 –4 ). TACC3 mRNA expression increased due to rs4558926 C > G and decreased DNA methylation levels. The CpG sites in the TACC3 promoter region were regulated by rs4558926. TACC3 knockdown decreased proliferation and senescence in colorectal cancer cells. In addition, subjects with high- TACC3 expression presented an immunosuppressive microenvironment. These findings provide insights into the involvement of genetic variants of cellular senescence genes in the development and progression of colorectal cancer.