Abstract 2575: Differentiation of NUT midline carcinoma by epigenomic reprogramming

Abstract

NUT midline carcinoma (NMC) is a lethal tumor defined by the presence of BRD-NUT fusion proteins that act by arresting differentiation. Here, we explore the mechanisms underlying the ability of BRD4-NUT to prevent squamous differentiation. We find that overexpression of the twin bromodomains of BRD4 or a portion of NUT that binds the histone acetyltransferase (HAT) p300 induces NMC cells to differentiate, suggesting a model in which BRD4-NUT sequesters HATs in areas of acetylated chromatin. Consistent with this idea, knockdown of BRD4-NUT caused global increases in histone acetylation, whereas enforced expression of BRD4-NUT had the opposite effect. Sequestration of HATs appears to occur in nuclear BRD4-NUT foci, which correspond to specific genomic regions that are rich in acetylated histones but transcriptionally inactive. Of therapeutic interest, treatment of NMC cells with histone deacetylase inhibitors (HDACi) dispersed nuclear foci, restored histone acetylation, induced NMC cells to differentiate in vitro, and had anti-tumor effects in NMC xenograft models. The data suggest that this rational therapeutic approach merits further evaluation in patients with NMC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2575. doi:10.1158/1538-7445.AM2011-2575

Nuclear protein in testis midline carcinoma in a Turkish boy: a case report

“…Nuclear protein in testis (NUT) midline carcinoma (NMC), also known as NUT carcinoma, is a poorly differentiated carcinoma characterized by translocations on chromosomes 15 and 19 [t(15;19)(q14;p13.1)] [1]. This genetic aberration occurs as a result of the fusion between the gene for NUT midline carcinoma family member 1 (NUTM1) on chromosome 15 and the gene for the bromodomain-containing protein 4 (BRD4) on chromosome 19.…”

“…This genetic aberration occurs as a result of the fusion between the gene for NUT midline carcinoma family member 1 (NUTM1) on chromosome 15 and the gene for the bromodomain-containing protein 4 (BRD4) on chromosome 19. The BRD4-NUT fusion oncogene, or the less frequently seen BRD3-NUT fusion oncogene, leads to the global hypoacetylation and suppression of the transcriptional gene required for differentiation [1,2]. Members of the BRD-NUT fusion protein family block epithelial differentiation and cell proliferation [2,3].…”