Investigation of the influence of BET proteins on NSD1 and their role in an epigenetic circuit influencing tumor viability in pancreatic cancer

尽管进行了大量的努力，胰腺导管腺癌（PDAC）患者仍然面临着惨淡的预后，并且没有有效的化疗。虽然最近的基因研究已经在PDAC中发现了许多致癌驱动突变，但可能用于治疗的突变尚未被描述。组蛋白的修饰调节染色质重塑并最终调控基因转录。因此，组蛋白修饰的畸变与多种癌症有关。正如宿主机构最近所表明的那样，表观遗传解读器，即bromo和外染色质接头，是PDAC细胞系增殖所必需的，并且与GLI， MYC和SHH一起，它们调节PDAC中的关键途径。初步研究表明，β -抑制显著降低了组蛋白赖氨酸甲基转移酶NSD1的表达，这是一种表观遗传因子。进一步的初步数据显示，NSD1的降低导致肿瘤生存能力降低，il - 6和STAT3水平降低。因此，我们假设(I) NSD1是一个bet应答基因，（II）通过IL6/STAT3介导的途径对PDAC发挥作用。因此，本项目将研究NSD1在PDAC中BET依赖程序中的作用，阐明其在PDAC中不依赖BET蛋白的作用，并分析NSD1对IL6/STAT3信号传导的影响。

Despite intensive efforts, patients with pancreatic ductal adenocarcinoma (PDAC) still face a dismal prognosis and effective chemotherapy is not available. While recent genetic investigations have identified numerous oncogenic driver mutations in PDAC, mutations that may be therapeutically targeted have not been described. Modifications of histone proteins regulate chromatin remodeling and ultimately gene transcription. Consequently, aberrations of histone modifications are associated with a variety of cancers. As recently shown by the host institution, bromo and extraterminal (BET) chromatin adaptors, epigenetic readers, are required for proliferation of PDAC cell lines and with GLI, MYC, and SHH, they regulate key pathways in PDAC. Preliminary work showed that BET-inhibition dramatically reduces the expression of the histone lysine methyltransferase NSD1, an epigenetic writer. Further preliminary data showed that reduction of NSD1 results in reduced tumor viability and reduced levels of IL6 and STAT3. Thus, we hypothesize that (I) NSD1 is a BET-responsive gene and (II) exerts its effects on PDAC via IL6/STAT3 mediated pathway. Accordingly, this project will investigate the role of NSD1 in the BET-dependent program in PDAC, elucidate its role in PDAC independent of BET proteins, and analyze the effects of NSD1 on IL6/STAT3 signaling.