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

GANCEDO, S; LAGOS, R; GONZALÉZ B; SAHORES, A; GHANEM CI; GOMÉZ, N; DAVIAO, C

Mar del Plata

Congreso; 63 Reunión Anual de la Sociedad Argentina de Investigación Cínica; 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) anddemethylases (TETs), are epigenetic modulators whose activity is frequentlyderegulated in various cancers including PDAC. In particular, HDAC1 and HDAC2have been shown to play an important role in the control of proliferation,apoptosis, differentiation, migration, and angiogenesis of PDAC cells. Themultidrug resistance-associated protein 4 MRP4/ABCC4 is a xenobiotictransporter involved in the regulation of cAMP signaling by extrusion to theextracellular compartment. MRP4 was found highly expressed in PDAC, and itsexpression correlates with increased proliferation and poor prognosis. MRP4overexpression in the PDAC cell line BxPC-3 increased proliferation, and cellinoculation in NGS mice produced xenografts with increased weight and poordifferentiation compared to mock tumors. Therefore, we aimed to analyze how MRP4overexpression collaborates in PDAC malignant epigenetic and transcriptionalsignature that enables tumor progression. We analyzed the expression of severalepigenetic modulators in MRP4-overexpressing BxPC-3 tumors (MRP4+), compared towild type tumors (WT) and tumors transfected with an empty vector (mock). Wefound increased HDAC1 and HDAC2 mRNA and protein levels, and concomitantlydecreased acetylation of H3K9ac, in MRP4+ compared to WT/mock (p<0.05). MRP4+tumors also showed increased mRNA expression of key enzymes involved inepigenetic control of cancer progression: Sirt1and Kdm1a (LSD1), involved in histonedeacetylation and demethylation, andDnmt1 and Tet1, linked toaberrant methylation/demethylation patterns in DNA. These findings suggest that,in pancreatic cancer, MRP4 contributes to the establishment of an aberrantepigenetic signature and altered transcriptional program which may drive cellstowards a proliferative and undifferentiated phenotype.