DNA polymerase beta modulates cancer progression via enhancing CDH13 expression by promoter demethylation

• Published in: Oncogene Vol. 39; no. 33; pp. 5507 - 5519
• Main Authors: Wang, Meina, Long, Kaili, Li, Enjie, Li, Lulu, Li, Binghua, Ci, Shusheng, He, Lingfeng, Pan, Feiyan, Hu, Zhigang, Guo, Zhigang
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.08.2020; Nature Publishing Group
• Subjects: 13/1; 14/35; 38/22; 38/77; 42/62; 45/22; 631/67/1857; 692/53/2423; A549 Cells; Angiogenesis; Animals; Apoptosis; Base excision repair; Breast cancer; Breast carcinoma; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cadherins - genetics; Cadherins - metabolism; Cancer; Cell adhesion; Cell adhesion & migration; Cell Biology; Cell migration; Demethylation; Deoxyribonucleic acid; Development and progression; Disease Models, Animal; Disease Progression; DNA; DNA Methylation; DNA polymerase; DNA Polymerase beta - genetics; DNA Polymerase beta - metabolism; DNA repair; DNA-directed DNA polymerase; Female; Gene expression; Genes; Genetic aspects; Genomic instability; Health aspects; Heterografts; Human Genetics; Humans; Internal Medicine; Invasiveness; Lung cancer; Lung carcinoma; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; MCF-7 Cells; Medicine; Medicine & Public Health; Metastases; Methylation; Mice; Mice, Nude; Mice, SCID; Oncology; Promoter Regions, Genetic; Tumors; Xenografts
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-020-1386-1

DNA polymerase β (Pol β) plays a critical role in DNA base excision repair (BER), which is involved in maintaining genomic stability and in the modulation of DNA demethylation. Numerous studies implicated deficiency of Pol β in the genomic instability and dysregulation of genes expression, leading to affecting initiation of cancer. However, the role of Pol β in cancer progression is still unclear. Here, we show that Pol β depresses migratory and invasive capabilities of both breast and lung carcinomas, which were evident in human breast and lung cancer cells, as well as in mouse xenograft tumors. On the molecular basis, overexpression of Pol β enhanced expression of CDH13, which show function on cell adhesion and migration. Knockdown of CDH13 restores the migratory, invasive capabilities and angiogenesis in tumor, which gets impaired by Pol β. According to the function of BER on modulation of DNA demethylation, our studies on CDH13 expression and the DNA methylation levels of CDH13 promoter suggested that Pol β promotes expression of CDH13 by augmenting DNA demethylation of CDH13 promoter. Our findings elucidated a novel possibility that Pol β impair cancer cell metastasis during cancer progression and shed light on the role of Pol β in cancer therapy.