Deciphering the role of NELFE in modulating MYC signaling in HCC

解读 NELFE 在 HCC 中调节 MYC 信号传导的作用

• 批准号: 10738028
• 负责人: Hien T. Dang
• 金额: $ 36.83万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-10 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10738028
• 关键词: Address; Affect; Antisense Oligonucleotides; Asian Pacific Islander; Binding; Binding Sites; Biochemical; Biological; Biological Assay; Biophysics; Black Populations; Cancer Etiology; Cell Nucleus; Cell Proliferation; Cell model; Cessation of life; Chromatin; Chromatin Remodeling Factor; Clinical; Data; Death Rate; Diagnosis; E protein; Etiology; Event; Exclusion; Exons; Gene Amplification; Gene Expression; Genetic Models; Genetic Transcription; Genotype; Goals; Hepatocarcinogenesis; Hispanic Populations; In Vitro; Invaded; Knock-in; Liquid substance; MYC Gene Amplification; MYC gene; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of liver; Maps; Mediating; Membrane; Molecular; Negative Finding; Not Hispanic or Latino; Nucleosomes; Oncogenic; Organelles; Patients; Phase; Phenotype; Physical condensation; Primary carcinoma of the liver cells; Process; Prognosis; Protein Isoforms; Proteins; Proto-Oncogenes; RNA Recognition Motif; RNA Splicing; Recombinant Proteins; Recurrent tumor; Reporting; Resolution; Role; SMARCB1 gene; SWI/SNF Family Complex; Signal Transduction; Testing; Therapeutic; Time; Tumor Burden; biophysical analysis; gene regulatory network; genome editing; in vivo; migration; multiple omics; negative elongation factor; novel; overexpression; potential biomarker; promoter; protein protein interaction; therapy development; tool; transcriptome; tumor; tumor heterogeneity; tumorigenesis; tumorigenic

ABSTRACT Hepatocellular carcinoma (HCC) is an aggressive tumor type with poor prognosis due to the diverse etiology, tumor heterogeneity, and the frequent late stage diagnosis. HCC is the fourth cause of cancer-related deaths in the world and is seen at higher rates among Hispanics, Blacks, and Asian Pacific Islanders compared with non- Hispanic whites. In the U.S, the rate of death from liver cancer has increased >40%. The proto-oncogene MYC is deregulated in ~80% of HCC. Yet, MYC remains to be an undruggable target. Although, the most common alteration is gene amplification (~30%), a significant proportion of MYC-driven HCCs have deregulated MYC signaling without concomitant MYC gene amplification. How MYC signaling is deregulated in HCC without concomitant MYC gene amplification is not understood. Our long-term goal is to understand the molecular basis for this phenotype to develop therapies to indirectly target MYC as a therapeutic strategy in HCC. The specific objective of this proposal is to confirm Negative Elongation Factor E (NELFE) as a central regulator of MYC signaling to promote HCC. The central hypothesis is deregulated NELFE modulates MYC signaling to promote HCC regardless of MYC status. We recently discovered the NELFE is over-expressed in 48% of HCC and is required for MYC-induced hepatocarcinogenesis. Preliminary data indicate NELFE alters nucleosome accessibility to modulate MYC-signaling. Moreover, we found NELFE localizes in the nucleus as biomolecular condensates, membraneless organelles that modulate transcription. Perturbation of NELFE condensates alters protein-protein interactions important for MYC signaling, suggesting NELFE condensation as a novel mechanism for MYC-induced HCC. We discovered a novel truncated NELFE isoform with anti-tumorigenic effects in advanced HCC. Isoform switching from FL NELFE to the truncated form via antisense oligonucleotides significantly reduced tumorigenic phenotypes and condensates. Here, we will use biophysical, biochemical, in vitro and in vivo assays to elucidate the role of NELFE on chromatin accessibility and biomolecular condensates as promoters of HCC through MYC signaling. Furthermore, we will use our established genetic models and antisense oligonucleotides to test the critical anti-tumorigenic function of the truncated NELFE isoform in HCC. Together, our proposed studies will define the novel role NELFE as a regulator of MYC as an essential player in the pathophysiological mechanisms of hepatocarcinogenesis and establish the function of the novel truncated NELFE protein.

摘要 肝细胞癌（HCC）是一种侵袭性肿瘤，由于病因多样，预后差， 肿瘤的异质性和频繁的晚期诊断。HCC是美国癌症相关死亡的第四大原因。 在西班牙裔、黑人和亚太岛民中， 西班牙裔白人在美国，肝癌的死亡率增加了40%以上。原癌基因MYC 在约80%的HCC中失调。然而，多年期承诺仍然是一个无法抗拒的目标。不过，最常见的 改变是基因扩增（~30%），显著比例的MYC驱动的HCC具有MYC失调 信号传导而不伴随MYC基因扩增。MYC信号如何在HCC中失调而不 伴随的MYC基因扩增尚不清楚。我们的长期目标是了解 对于这种表型，开发间接靶向MYC的疗法作为HCC的治疗策略。具体 本提案的目的是确认负延伸因子E（NELFE）作为MYC的中心调节因子 信号传导促进HCC。中心假设是去调节的NELFE调节MYC信号传导以促进MYC的表达。 无论MYC状态如何，HCC。我们最近发现NELFE在48%的HCC中过度表达， MYC诱导的肝癌发生所必需的。初步数据表明NELFE改变了核小体 调节MYC信号传导的可接近性。此外，我们还发现NELFE作为生物分子定位于细胞核内 浓缩物，调节转录的无膜细胞器。NELFE凝聚的扰动改变了 蛋白质-蛋白质相互作用对MYC信号传导很重要，这表明NELFE缩合是一种新的机制 MYC诱导的HCC。我们发现了一种新的截短的NELFE同种型，具有抗肿瘤作用， 晚期HCC通过反义寡核苷酸将FL NELFE的亚型转换为截短形式 显着减少肿瘤发生表型和冷凝物。在这里，我们将使用生物物理，生物化学， 体外和体内试验，以阐明NELFE对染色质可及性和生物分子凝聚物的作用 通过MYC信号传导作为HCC的启动子。此外，我们将使用我们建立的遗传模型， 反义寡核苷酸来测试截短的NELFE同种型在HCC中的关键抗肿瘤发生功能。 总之，我们提出的研究将定义NELFE作为MYC调节剂的新作用， 肝癌发生的病理生理机制，并建立新的截短的功能， NELFE蛋白。