1 Department of Molecular and Cell Biology, Boston University Henry M. Goldman School of Dental Medicine, Boston, MA, USA.
J Dent Res. 2019 Mar;98(3):268-276. doi: 10.1177/0022034518816947. Epub 2019 Jan 7.
The most common type of head and neck cancer, head and neck squamous cell carcinoma (HNSCC), can develop therapeutic resistance that complicates its treatment. The 5-y survival rate for HNSCC remains at ~50%, and improving these outcomes requires a better understanding of the pathogenesis of HNSCC. Studies of HNSCC using in vitro, ex vivo, and in vivo approaches provide a novel conceptual framework based on epigenetic mechanisms for developing future clinical applications. Normal oral tissues are influenced by environmental factors that induce pathological changes affecting the network of epigenetic enzymes and signaling pathways to induce HNSCC growth and metastasis. Although various epigenetic regulator families, such as DNA methyltransferases, ten-eleven translocation proteins, histone acetyltransferases, histone deacetylases, BET bromodomain proteins, protein arginine methyltransferases, histone lysine methyltransferases, and histone lysine demethylases, have a role in diverse cancers, specific members have a function in HNSCC. Recently, lysine-specific demethylases have been identified as a potential, attractive, and novel target of HNSCC. Lysine-specific demethylase 1 (LSD1) expression is inappropriately upregulated in HNSCC and an orthotopic HNSCC mouse model. LSD1 can demethylate lysine at specific histone positions to repress gene expression or stimulate transcription, indicating a dual and context-dependent role in transcriptional regulation. Our study showed that LSD1 promotes HNSCC growth and metastasis. Pharmacological attenuation of LSD1 inhibits orthotopic and patient-derived HNSCC xenograft growth-specific target genes and signaling pathways. This review provides recent evidence demonstrating the function of epigenetic regulator enzymes in HNSCC progression, including potential therapeutic applications for such enzymes in combination and immunotherapy.
头颈部鳞状细胞癌（HNSCC）是最常见的头颈部癌症类型，可产生治疗耐药性，从而使治疗复杂化。HNSCC 的 5 年生存率仍保持在约 50%，为改善这些结果，需要更好地了解 HNSCC 的发病机制。采用体外、离体和体内方法研究 HNSCC，为开发未来的临床应用提供了一种基于表观遗传机制的新的概念框架。正常口腔组织受到环境因素的影响，这些因素会导致病理性变化，影响表观遗传酶和信号通路网络，从而诱导 HNSCC 的生长和转移。尽管各种表观遗传调节剂家族，如 DNA 甲基转移酶、十号十一号转位蛋白、组蛋白乙酰转移酶、组蛋白去乙酰化酶、BET 溴结构域蛋白、蛋白质精氨酸甲基转移酶、组蛋白赖氨酸甲基转移酶和组蛋白赖氨酸去甲基酶，在各种癌症中都有作用，但特定成员在 HNSCC 中具有功能。最近，赖氨酸特异性去甲基酶已被确定为 HNSCC 的一个潜在、有吸引力和新颖的靶点。HNSCC 和原位 HNSCC 小鼠模型中，赖氨酸特异性去甲基酶 1（LSD1）表达不适当地上调。LSD1 可以在特定的组蛋白位置去甲基化赖氨酸，以抑制基因表达或刺激转录，表明其在转录调控中具有双重和上下文相关的作用。我们的研究表明，LSD1 促进 HNSCC 的生长和转移。药理学减弱 LSD1 抑制原位和患者来源的 HNSCC 异种移植物生长的特异性靶基因和信号通路。本综述提供了最近的证据，证明了表观遗传调节剂酶在 HNSCC 进展中的作用，包括这些酶在联合和免疫治疗中的潜在治疗应用。
