Zygote arrest 1 like (ZAR2) and cell cycle in breast cancer cells

Abstract

ZAR2 is a novel RNA-binding C4 zinc finger containing protein, with cell cycle dependent differential expression and nuclear/ cytosolic localization. We observed that ZAR2 expression is relatively lower in triple negative breast cancer cells (TNBC) compared to non-TNBC and forced expression in TNBC cells inhibit their growth and invasiveness. Knocking down ZAR2 in non-TNBC cells increased their growth and invasiveness. Our studies showed that ZAR2, is inhibited by a c-Myc regulated miRNA, hsa-miR-130a-5p. Studies demonstrate that ZAR2 localizes in the RNA processing P-bodies and regulates the turnover of maternal WEE1 mRNA in developing oocytes. WEE1 is a tyrosine kinase, which regulates G2/M checkpoint in cell cycle, is over-expressed in various cancer types and is associated with resistance development to DNA-damaging agents. WEE1, is identified as a potential molecular target for TNBC. WEE1 inhibition is exclusively toxic for cancer cells and does not harm healthy cells. Major objective of the proposed research is to evaluate the potential of a novel protein ZAR2 as a modulator of G2-M checkpoint and therapeutic target in breast cancer. c-Myc mediated downregulation of ZAR2 expression via hsa-miR-130a-5p, results in increased levels of WEE1 protein in breast cancer cells, increased proliferation and faster progression through cell cycle.