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

Abstract

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.

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Fig. 1: Pol β expression correlates with cancer progression and cancer cells motility.
Fig. 2: Pol β depresses tumor metastasis and invasion in in xenograft mouse model.
Fig. 3: Deficiency of Pol β enhances tumor metastasis.
Fig. 4: Pol β suppresses cancer cell migration by regulating gene expression of CDH13.
Fig. 5: Pol β suppression of tumor cell motility depends on CDH13.
Fig. 6: Deletion of CDH13 restores the repressed angiogenesis by Pol β.
Fig. 7: Pol β impedes DNA methylation of CDH13 promoter leading to promote CDH13 expression.

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Acknowledgements

The authors would like to thank Dr. Binghui Shen (Beckman Research Institute, City of Hope, Duarte, CA, USA) for the MEF cell lines. This work was supported by the National Natural Science Foundation of China (81872284), the Natural Science Foundation of Colleges and Universities in Jiangsu Province (19KJA180010), and the Priority Academic Program Development of Jiangsu Higher Education Institutions.

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Correspondence to Zhigang Hu or Zhigang Guo.

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Wang, M., Long, K., Li, E. et al. DNA polymerase beta modulates cancer progression via enhancing CDH13 expression by promoter demethylation. Oncogene 39, 5507–5519 (2020). https://doi.org/10.1038/s41388-020-1386-1

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