文章：

NSD1在HPV阴性头颈部鳞状细胞癌中对PIP4K2B蛋白的调控作用

PIP4K2B Protein Regulation by NSD1 in HPV-Negative Head and Neck Squamous Cell Carcinoma

原文发布日期：17 March 2024

DOI: 10.3390/cancers16061180

类型: Article

开放获取: 是

英文摘要：

Head and neck squamous cell carcinoma (HNSCC) ranks among the most prevalent global cancers. Despite advancements in treatments, the five-year survival rate remains at approximately 66%. The histone methyltransferase NSD1, known for its role in catalyzing histone H3 lysine 36 di-methylation (H3K36me2), emerges as a potential oncogenic factor in HNSCC. Our study, employing Reverse Phase Protein Array (RPPA) analysis and subsequent validation, reveals that PIP4K2B is a key downstream target of NSD1. Notably, PIP4K2B depletion in HNSCC induces downregulation of the mTOR pathway, resulting in diminished cell growth in vitro. Our investigation highlights a direct, positive regulatory role of NSD1 on PIP4K2B gene transcription through an H3K36me2-dependent mechanism. Importantly, the impact of PIP4K2B appears to be context-dependent, with overexpression rescuing cell growth in laryngeal HNSCC cells but not in tongue/hypopharynx cells. In conclusion, our findings implicate PIP4K2B as a novel NSD1-dependent protein in HNSCC, suggesting its potential significance for laryngeal cancer cell survival. This insight contributes to our understanding of the molecular landscape in HNSCC and establishes PIP4KB as a promising target for drug development.

摘要翻译： 

头颈部鳞状细胞癌（HNSCC）是全球范围内最常见的癌症之一。尽管治疗方法有所进展，其五年生存率仍维持在约66%。组蛋白甲基转移酶NSD1以催化组蛋白H3第36位赖氨酸二甲基化（H3K36me2）而闻名，在HNSCC中显示出作为潜在致癌因子的作用。本研究通过反相蛋白质阵列（RPPA）分析及后续验证，揭示PIP4K2B是NSD1的关键下游靶点。值得注意的是，在HNSCC中敲低PIP4K2B会诱导mTOR通路下调，从而导致体外细胞生长减弱。我们的研究进一步表明，NSD1通过H3K36me2依赖机制对PIP4K2B基因转录具有直接的正向调控作用。重要的是，PIP4K2B的作用具有环境依赖性：其在喉部HNSCC细胞中的过表达能挽救细胞生长，但在舌/下咽部细胞中则无此效果。综上所述，本研究发现PIP4K2B是HNSCC中一种新型的NSD1依赖性蛋白，提示其对喉癌细胞存活具有潜在重要意义。这一发现深化了我们对HNSCC分子机制的理解，并确立了PIP4K2B作为药物开发的潜在靶点。

原文链接：

PIP4K2B Protein Regulation by NSD1 in HPV-Negative Head and Neck Squamous Cell Carcinoma