Analysis of MRP4/ABCC4-induced epigenetic signature in pancreatic cancer

ANA SAHORES; BETINA GONZALEZ; SAMANTA GANCEDO; CARLOS DAVIO; NATALIA GÓMEZ

Mar del Plata

Congreso; LXIV Reunión Científica anual de la Sociedad Argentina de Investigación Clínica; 2019

SAIC

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with a dismal prognosis. Histone deacetylases (HDACs) and demethylases (KDMs), as well as DNA methylases (DNMTs) and demethylases (TETs), are epigenetic modulators whose activity is frequently deregulated in various cancers including PDAC. In particular, HDAC1 and HDAC2 have been shown to play an important role in the control of proliferation, apoptosis, differentiation, migration, and angiogenesis of PDAC cells. The multidrug resistance-associated protein 4 MRP4/ABCC4 is a xenobiotic transporter involved in the regulation of cAMP signaling by extrusion to the extracellular compartment. MRP4 was found highly expressed in PDAC, and its expression correlates with increased proliferation and poor prognosis. MRP4 overexpression in the PDAC cell line BxPC-3 increased proliferation, and cell inoculation in NGS mice produced xenografts with increased weight and poor differentiation compared to mock tumors. Therefore, we aimed to analyze how MRP4 overexpression collaborates in PDAC malignant epigenetic and transcriptional signature that enables tumor progression. We analyzed the expression of several epigenetic modulators in MRP4-overexpressing BxPC-3 tumors (MRP4+), compared to wild type tumors (WT) and tumors transfected with an empty vector (mock). We found increased HDAC1 and HDAC2 mRNA and protein levels, and concomitantly decreased acetylation of H3K9ac, in MRP4+ compared to WT/mock (p