ZNF331 Represses the Proliferation of Head and Neck Squamous Cell Carcinoma via Co-Repressor TRIM28.

IF 2.9 3区医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE

Oral diseases Pub Date : 2024-11-25 DOI:10.1111/odi.15209

Ju Li, Hao Cheng, Yong Zhao, Yunkang Wang, Chen Gong, Renguo Gong, Yan Li

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引用次数: 0

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.

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研究目的本研究旨在探讨锌指蛋白331（ZNF331）（一种含KRAB结构域的转录抑制因子）在头颈部鳞状细胞癌（HNSCC）中的调控作用：分析了癌症基因组图谱（TCGA）-HNSCC的数据。通过体外操纵 ZNF331 的表达和体内异种移植实验，探讨了 ZNF331 在 HNSCC 细胞增殖、细胞周期进展及其互作蛋白中的作用。通过评估ZNF331启动子甲基化和DNA甲基转移酶（DNMT）敲除的影响，研究了ZNF331失调的表观遗传学机制：结果：ZNF331表达较高的患者的无进展间期（PFI）明显改善。ZNF331过表达可抑制HNSCC细胞增殖并诱导G2/M停滞，而其敲除可增强致癌特征。ZNF331 能下调 DDX5、EIF5A 和 SET 等致癌基因的表达。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 的表达受到 DNMT3B 介导的启动子超甲基化的抑制。选择性敲除 DNMT3B（而非 DNMT3A）可恢复 ZNF331 的表达：结论：ZNF331在HNSCC中是一种潜在的肿瘤抑制因子，其通过DNMT3B介导的高甲基化失活可能会导致HNSCC肿瘤发生。通过表观遗传靶向疗法恢复 ZNF331 的表达可能会为 HNSCC 的治疗提供一种新策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Oral diseases 医学-牙科与口腔外科

CiteScore

7.60

自引率

5.30%

发文量

325

审稿时长

4-8 weeks

期刊介绍： Oral Diseases is a multidisciplinary and international journal with a focus on head and neck disorders, edited by leaders in the field, Professor Giovanni Lodi (Editor-in-Chief, Milan, Italy), Professor Stefano Petti (Deputy Editor, Rome, Italy) and Associate Professor Gulshan Sunavala-Dossabhoy (Deputy Editor, Shreveport, LA, USA). The journal is pre-eminent in oral medicine. Oral Diseases specifically strives to link often-isolated areas of dentistry and medicine through broad-based scholarship that includes well-designed and controlled clinical research, analytical epidemiology, and the translation of basic science in pre-clinical studies. The journal typically publishes articles relevant to many related medical specialties including especially dermatology, gastroenterology, hematology, immunology, infectious diseases, neuropsychiatry, oncology and otolaryngology. The essential requirement is that all submitted research is hypothesis-driven, with significant positive and negative results both welcomed. Equal publication emphasis is placed on etiology, pathogenesis, diagnosis, prevention and treatment.