ZNF331 Represses the Proliferation of Head and Neck Squamous Cell Carcinoma via Co‐Repressor TRIM28
Ju Li, Hao Cheng, Yong Zhao, Yunkang Wang, Chen Gong, Renguo Gong, Yan Li ABSTRACT
Objective
This study aims to explore the regulatory effect of Zinc Finger Protein 331 (ZNF331), a KRAB domain‐containing transcriptional repressor, in Head and Neck Squamous Cell Carcinoma (HNSCC).
Materials and Methods
Data from The Cancer Genome Atlas (TCGA)‐HNSC were analyzed. The roles of ZNF331 in HNSCC cell proliferation, cell cycle progression, and its interacting proteins were explored through in vitro manipulation of ZNF331 expression and in vivo xenograft experiments. The epigenetic mechanisms underlying ZNF331 dysregulation were investigated by assessing its promoter methylation and the effects of DNA methyltransferase (DNMT) knockdown.
Results
Patients with higher ZNF331 expression had a significantly improved progression‐free interval (PFI). ZNF331 overexpression inhibits HNSCC cell proliferation and induces G2/M arrest, while its knockdown enhances oncogenic features. ZNF331 can downregulate the expression of oncogenes such as DDX5, EIF5A, and SET. ZNF331's tumor‐suppressive activity requires TRIM28, a universal co‐repressor of KRAB‐ZNF proteins. ZNF331 expression is suppressed by DNMT3B‐mediated promoter hypermethylation. Selective knockdown of DNMT3B, but not DNMT3A, restored ZNF331 expression.
Conclusions
ZNF331 acts as a potential tumor suppressor in HNSCC, whose inactivation through DNMT3B‐mediated hypermethylation may contribute to HNSCC tumorigenesis. Restoring ZNF331 expression through targeted epigenetic therapies may offer a novel strategy for the treatment of HNSCC.