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）是一种侵袭性肿瘤，由于病因多样，预后较差，肿瘤异质性和频繁的晚期诊断。 HCC 是癌症相关死亡的第四大原因与非非裔美国人相比，西班牙裔、黑人和亚太岛民的患病率更高西班牙裔白人。在美国，肝癌死亡率增加了 40% 以上。原癌基因 MYC 在大约 80% 的 HCC 中放松管制。然而，MYC 仍然是一个不可抗拒的目标。虽然，最常见的改变是基因扩增（~30%），很大一部分 MYC 驱动的 HCC 已失调 MYC 信号传导无需伴随 MYC 基因扩增。 MYC 信号如何在 HCC 中解除管制而无需伴随的 MYC 基因扩增尚不清楚。我们的长期目标是了解分子基础针对这种表型，开发间接靶向 MYC 的疗法作为 HCC 的治疗策略。具体的该提案的目的是确认负伸长因子 E (NELFE) 作为 MYC 的中央调节器信号传导促进 HCC。核心假设是 NELFE 调节 MYC 信号传导以促进 HCC，无论 MYC 状态如何。我们最近发现 NELFE 在 48% 的 HCC 中过度表达，并且 MYC 诱导的肝癌发生所需的。初步数据表明 NELFE 改变核小体调节 MYC 信号传导的可及性。此外，我们发现 NELFE 作为生物分子定位于细胞核中。凝结物，调节转录的无膜细胞器。 NELFE 凝聚物的扰动改变蛋白质-蛋白质相互作用对 MYC 信号转导很重要，表明 NELFE 缩合是一种新机制用于 MYC 诱导的 HCC。我们发现了一种新型截短的 NELFE 亚型，具有抗肿瘤作用晚期肝癌。通过反义寡核苷酸从 FL NELFE 异构体转换为截短形式显着减少致瘤表型和凝体。在这里，我们将使用生物物理、生物化学、体外和体内实验阐明 NELFE 对染色质可及性和生物分子凝聚体的作用通过 MYC 信号传导作为 HCC 的启动子。此外，我们将利用我们已建立的遗传模型反义寡核苷酸测试截短的 NELFE 同种型在 HCC 中的关键抗肿瘤功能。总之，我们提出的研究将定义 NELFE 作为 MYC 调节者的新角色，作为 MYC 的重要参与者肝癌发生的病理生理机制并建立新型截短的功能 NELFE 蛋白。