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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的肝细胞癌（HCC）是一种侵略性肿瘤类型，由于病因多样，预后不良，肿瘤异质性和频繁的晚期诊断。 HCC是癌症相关死亡的第四个原因在西班牙裔，黑人和亚洲太平洋岛民中，与非 - 西班牙裔白人。在美国，肝癌的死亡率> 40％。原始癌基因在HCC的约80％中被放松管制。但是，MYC仍然是一个不足的目标。虽然，最常见改变是基因扩增（〜30％），大部分MYC驱动的HCC已失控的MYC 没有伴随MYC基因扩增的信号传导。 MYC信号如何在没有HCC中放置尚不清楚伴随的MYC基因扩增。我们的长期目标是了解分子基础为了使这种表型开发疗法，以间接将MYC作为HCC的治疗策略。具体该提议的目的是确认负伸长因子E（NELFE）为MYC的中心调节剂信号传导以促进HCC。中央假设由NELFE放松调节，可调节MYC信号传导以促进 HCC不管MYC身份如何。我们最近发现Nelfe在HCC的48％中过表达，并且 MYC诱导的肝癌发生所必需的。初步数据表明Nelfe改变了核小体可访问性调节MYC信号。此外，我们发现Nelfe定位在核中，作为生物分子凝结物，调节转录的无膜细胞器。 Nelfe冷凝物的扰动改变蛋白质 - 蛋白质相互作用对于MYC信号传导很重要，表明Nelfe凝结是一种新型机制对于MYC引起的HCC。我们发现了一种新型的截短的Nelfe同工型高级HCC。同工型通过反义寡核苷酸从FL Nelfe转换为截短的形式显着降低了肿瘤性表型和冷凝水。在这里，我们将在体外和体内测定，以阐明Nelfe在染色质可及性和生物分子冷凝物上的作用通过MYC信号作为HCC的启动子。此外，我们将使用我们已建立的遗传模型和反义寡核苷酸测试HCC中截短的NELFE同工型的关键抗肿瘤功能。我们提出的研究一起将把新颖的角色定义为MYC的调节者，是肝癌发生的病理生理机制并建立了新颖的截断功能 Nelfe蛋白。