EHF is a novel regulator of cellular redox metabolism and predicts patient prognosis in HNSCC.
EHF is a novel regulator of cellular redox metabolism and predicts patient prognosis in HNSCC.
复制标题
EHF是细胞氧化还原代谢的新型调节剂，可以预测HNSCC的患者预后。
作者：
头颈部鳞状细胞癌（HNSCC）是一种发病率和死亡率相对较高的异质性疾病。由于缺乏有效的治疗方法，高复发率和部分由肿瘤异质性驱动的耐药性，导致诊断为这种癌症的患者预后不良。导致疾病多样性的关键调控因素在很大程度上仍然难以捉摸，这一事实进一步加剧了这一问题。在这里，我们已经确定EHF是ETS转录因子家族的一个重要成员，该家族在正常口腔组织中高度表达，但在HNSCC进展过程中丢失。有趣的是，HNSCC肿瘤和细胞系表现出EHF高表达和低表达的两分法，肿瘤保留EHF表达的患者预后明显更好，提示EHF可能具有抑制肿瘤的作用。为了解决这个问题，我们进行了功能的获得和丧失研究，并利用大量和单细胞癌症基因组数据集，通过HNSCC细胞系的rna测序（RNA-seq）、染色质免疫沉淀和下一代测序（ChIP-seq）实验，确定了全球EHF靶点。这些机制研究表明，EHF作为一种广泛的代谢过程的调节剂，特别针对氧化还原稳态的调节剂，如NRF2和SOX2。我们的免疫染色结果证实了EHF和SOX2在HNSCC肿瘤中相互排斥的表达模式，并提示这两个因素在肿瘤微环境中建立离散代谢状态的可能作用。综上所述，EHF可以作为一种新的预后指标，用于对HNSCC患者进行分类，以便进行可操作的靶向治疗干预。ehf驱动的氧化还原代谢途径中关键基因的抑制将HNSCC患者分为不同的组，并影响患者的预后。
Head and Neck Squamous Cell Carcinoma (HNSCC) is a heterogeneous disease with relatively high morbidity and mortality rates. The lack of effective therapies, high recurrence rates and drug resistance driven in part, by tumor heterogeneity, contribute to the poor prognosis for patients diagnosed with this cancer. This problem is further exacerbated by the fact that key regulatory factors contributing to the disease diversity remains largely elusive. Here, we have identified EHF as an important member of the ETS family of transcription factors that is highly expressed in normal oral tissues, but lost during HNSCC progression. Interestingly, HNSCC tumors and cell lines exhibited a dichotomy of high and low EHF expression, and patients whose tumors retained EHF expression showed significantly better prognosis, suggesting a potential tumor suppressive role for EHF. To address this, we have performed gain and loss of function studies and leveraged bulk and single-cell cancer genomic datasets to identify global EHF targets by RNA-sequencing (RNA-seq) and Chromatin Immunoprecipitation and next generation sequencing (ChIP-seq) experiments of HNSCC cell lines. These mechanistic studies have revealed that EHF, acts as a regulator of a broad spectrum of metabolic processes, specifically targeting regulators of redox homeostasis such as NRF2 and SOX2. Our immunostaining results confirm the mutually exclusive expression patterns of EHF and SOX2 in HNSCC tumors and suggest a possible role for these two factors in establishing discrete metabolic states within the tumor microenvironment. Taken together, EHF may serve as a novel prognostic marker for classifying HNSCC patients for actionable and targeted therapeutic intervention. EHF-driven repression of key genes in redox metabolic pathways stratifies HNSCC patients into distinct groups and influences patient outcome.
影响因子：
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作者：
Escamilla-Hernandez R;Chakrabarti R;Romano RA;Smalley K;Zhu Q;Lai W;Halfon MS;Buck MJ;Sinha S
通讯作者：
Sinha S