TET2 inhibits tumorigenesis of breast cancer cells by regulating caspase-4.

Epigenetic regulators have been shown to influence breast cancer progression. However, the detailed mechanism by which TET2 plays the suppressive role in tumorigenesis remains not completely understood. We employed RT-qPCR and westernblot to examine genes expression. Next, the bisulphite sequencing PCR was used to determine the methylation level at CASP4 promoter in the cells. Phenotypically, we utilized growth curve analysis, colony formation in soft agar and xenograft tumor assay to assess tumorigenesis of MCF-7 cell. We found that TET2 knockout enhanced colony formation ability and in vivo tumor formation ability of MCF-7 cell, whereas TET2 depletion not affected the growth rate of MCF-7 cell in the culture. Mechanistically, TET2 loss led to a significant decrease in caspase-4 expression possibly via increasing DNA methylation of CASP4 promoter in MCF-7 cell. To validate, TET2 overexpression led to higher level of caspase-4 in MDA-MB-231 and 293T cells, which was dependent on TET2 enzymatic activity. Finally, we observed that caspase-4 could revert, at least partially, TET2 deletion-induced tumorigenesis of MCF-7. In summary, we reveal a novel mechanism that TET2 suppresses tumorigenesis of breast cancer cells through caspase-4. Our findings will facilitate development of new diagnostic markers or therapeutical therapies for breast cancer.