FEZF2 inhibits the growth of triple-negative breast cancer cells through EZH2/PD-L1 and enhances anti-tumor immunity in vivo

Background Triple-negative breast cancer (TNBC) is characterized by high aggressiveness, heterogeneity, and poor prognosis. Programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors, a crucial type of immune checkpoint inhibitor therapy, have been proven to be a promising strategy for the TNBC treatment. Forebrain embryonic zinc finger 2 (FEZF2) is dysregulated in various cancers and participates in the tumor progression. However, its role and mechanism in TNBC remain unknown. Objectives To investigate whether FEZF2 is involved in the progression of TNBC via EZH2/PD-L1 axis. Results The expression of FEZF2 was downregulated in TNBC. Overexpression of FEZF2 reduced cell viability and enhanced cell apoptosis in both MDA-MB-231 and BT-549 cells. Meanwhile, upregulation of FEZF2 decreased the relative protein expression of EZH2 and PD-L1, which was restored by overexpression of EZH2 in both cells. Moreover, overexpression of PD-L1 neutralized the inhibitory effect of the FEZF2 overexpression on the cell viability in MDA-MB-231 and BT-549 cells. Furthermore, overexpression of FEZF2 reduced the tumor weight and volume, and increased numbers of CD8 + tumor-infiltrating lymphocytes in xenografted mice. Conclusion Overexpression of FEZF2 inhibited the proliferation and enhanced the apoptosis of TNBC cells through EZH2/PD-L1 axis, as well as promoted anti-tumor immunity in vivo.