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

尽管付出了巨大的努力，胰腺导管腺癌（PDAC）患者仍然面临着令人沮丧的预后，并且没有有效的化疗。虽然最近的遗传学研究已经确定了PDAC中的许多致癌驱动突变，但尚未描述可能具有治疗靶向的突变。组蛋白的修饰调节染色质重塑并最终调节基因转录。因此，组蛋白修饰的畸变与多种癌症相关。如最近由主办机构所示，溴和末端外（BET）染色质衔接子（表观遗传阅读器）是PDAC细胞系增殖所需的，并且与GLI、MYC和SHH一起，它们调节PDAC中的关键通路。初步工作表明，BET抑制显着降低组蛋白赖氨酸甲基转移酶NSD 1，表观遗传作家的表达。进一步的初步数据显示，NSD 1的减少导致肿瘤活力降低和IL 6和STAT 3水平降低。因此，我们假设（I）NSD 1是BET应答基因，并且（II）通过IL 6/STAT 3介导的途径对PDAC发挥作用。因此，本项目将研究NSD 1在PDAC中BET依赖性程序中的作用，阐明其在PDAC中不依赖于BET蛋白的作用，并分析NSD 1对IL 6/STAT 3信号转导的影响。

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.