Zinc finger factor ZNF121 is a MYC-interacting protein functionally affecting MYC and cell proliferation in epithelial cells.

MYC is a potent oncoprotein that modulates multiple cellular processes including proliferation, apoptosis, differentiation, stemness, senescence, and migration. Functioning primarily as a transcriptional factor, MYC interacts with a large number of proteins, and identification and characterization of MYC-interacting proteins are important for understanding how MYC functions. In this study, we used different systems to demonstrate that a novel zinc finger transcription factor, ZNF121, physically interacted with MYC, and the interaction involved their N-terminal regions. Overexpression of ZNF121 increased, while its knockdown decreased, the expression of MYC in multiple epithelial cell lines, and MYC had similar effects on ZNF121 expression. An expression correlation was also detectable in a panel of epithelial cell lines and a cohort of human breast cancer tissues. Functionally, knockdown of ZNF121 in several breast epithelial cell lines attenuated the expressions of MYC and its target genes (e.g., EGR1, CDC2, and nucleolin) and slowed cell proliferation, accompanied by cell cycle arrest in the G1 phase and expression alteration of cell cycle regulators (cyclin D1, p14 and p21). Analysis of publically available databases showed that ZNF121 expression is up-regulated in human breast cancer, and the up-regulation significantly associates with worse patient survival in the luminal A subtype of breast cancer. These findings establish ZNF121 as a MYC-interacting protein with functional effects on MYC and cell proliferation.