Li Ju, Cheng Hao, Zhao Yong, Wang Yunkang, Gong Chen, Gong Renguo, Li Yan
Department of Stomatology, The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, China.
Vincent Mary School of Engineering, Science and Technology Assumption University of Thailand, Bangkok, Thailand.
Oral Dis. 2025 Apr;31(4):1178-1188. doi: 10.1111/odi.15209. Epub 2024 Nov 25.
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).
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.
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.
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.
本研究旨在探讨含KRAB结构域的转录抑制因子锌指蛋白331（ZNF331）在头颈部鳞状细胞癌（HNSCC）中的调控作用。
分析了来自癌症基因组图谱（TCGA）-HNSC的数据。通过体外操纵ZNF331表达和体内异种移植实验，探讨ZNF331在HNSCC细胞增殖、细胞周期进程及其相互作用蛋白中的作用。通过评估其启动子甲基化和DNA甲基转移酶（DNMT）敲低的影响，研究ZNF331失调的表观遗传机制。
ZNF331表达较高的患者无进展生存期（PFI）显著改善。ZNF331过表达抑制HNSCC细胞增殖并诱导G2/M期阻滞，而其敲低则增强致癌特性。ZNF331可下调DDX5、EIF5A和SET等癌基因的表达。ZNF331的肿瘤抑制活性需要TRIM28，它是KRAB-ZNF蛋白的通用共抑制因子。ZNF331的表达受DNMT3B介导的启动子高甲基化抑制。选择性敲低DNMT3B而非DNMT3A可恢复ZNF331的表达。
ZNF331在HNSCC中作为一种潜在的肿瘤抑制因子发挥作用，其通过DNMT3B介导高甲基化而失活可能促成HNSCC的肿瘤发生。通过靶向表观遗传疗法恢复ZNF331的表达可能为HNSCC的治疗提供一种新策略。
