p53 and miR-215 form a positive feedback regulatory mechanism to regulate cell cycle control. The expression of p53 was induced by the suppression of DTL, a critical component of the e CUL4A–DDB1 E3 ubiquitin ligase complex, along with the p53 down stream gene p21. The elevated p53 in turn up-regulates the expression of miR-215. In addition, to DTL, miR-215 also suppresses the expression of TS, DHFR, CDC7, MCM3, MCM10. miR-215 triggers cell cycle arrest at the G2/M phase without triggering cell death, which contribute to chemoresistance to TS and DHFR inhibitors in CSCs. miR-215 also mediates EMT transition by targeting ZEB2 via TGFβ signaling pathway.