Kindlin-2 interacts with and stabilizes DNMT1 to promote breast cancer development

Abstract Integrin-interacting protein Kindlin-2, as a focal adhesion protein, promotes growth and progression of breast cancer. However, the precise mechanism that underlie the role of Kindlin-2 in breast cancer is elusive. Here, we report that the expression of Kindlin-2 positively correlated with DNA methyltransferase 1(DNMT1) in breast cancer patients. Further, we found that DNMT1 was upregulated in mammary gland tissues of mammary specific Kindlin-2 transgenic mice. More importantly, high expression of DNMT1 was observed in mammary tumors formed by Kindlin-2 transgenic mice. On the basis of these observations, DNMT inhibitor 5-aza-CdR was used and found its treatment strongly decreased Kindlin-2-induced breast cancer cell proliferation and migration. Mechanistically, Kindlin-2 increased the stability of DNA methyltransferase DNMT1 through interaction with DNMT1 and methylated CpG islands in the E-cadherin promoter. Kindlin-2 increased the occupancy of DNMT1 at E-cadherin promoter, thereby suppressing E-cadherin expression. Taken together, our data reveal that Kindlin-2 promotes breast cancer development by enhancing the stability of DNMT1.