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

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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.