To examine the impact of 4-nonylphenol (4-NP), on the expression of polycomb repressive complexes and cellular proliferation. Cell proliferation assays, quantitative PCR, Western blotting, luciferase reporter assay, chromatin immunoprecipitation-quantitative PCR were used for the study. The 4-NP at 100 nM concentration significantly increased proliferation of MCF-7 cells. It enhanced the expression of RNF2-BMI1 and EZH2-SUZ12 and concomitantly increased H2AK119ub1 and H3K27me3 repressive marks at p21 proximal promoter resulting in its reduced expression. Selective inhibition of RNF2 or EZH2 reverted the 4-NP action. The phospho-CREB, SP1 and E2F-1 are enriched at proximal promoter of RNF2 and EZH2 and cyclin D1, but not p21. The 4-NP-mediated upregulation of RNF2 and EZH2 resulted in epigenetic silencing of p21.