TARGETING POST-PRENYLATION PROCESSING IN CANCER: STUDY OF THE ROLE OF ICMT IN TUMOR PROGRESSION

GIRARDINI, JAVIER E.; CAROLINA DI BENEDETTO; CAROLINA ROSSI; MENACHO MARQUÉZ MAURICIO; BORINI ETICHETTI, CARLA M.

BUENOS AIRES

Congreso; REUNIÓN CONJUNTA DE SOCIEDADES DE BIOCIENCIAS; 2017

Most human cancers inactivate the tumor suppressor p53 throughmissense mutations, leading to the abundant expression of fulllengthpoint mutant proteins. p53 mutants not only lose the tumorsuppressor function but also may acquire novel activities that promotetumor progression. Despite evidences showing that mutantp53 enhances tumor aggressiveness, the mechanisms underlyingthis activity are still poorly understood. Even if the mutation abrogatesthe ability to act as a transcription factor, point mutants altergene expression through mechanisms that are not well characterized.In order to characterize those mechanisms we studied theeffects of mutant p53 on gene expression. Basing on data from microarrayanalysis on MDA-MB-231 Triple Negative Breast Cancercells we selected candidate genes and we confirmed the effect ofmutant p53 in qRT-PCR assays. We focused on ICMT, which regulatessubcellular localization and function of proteins with a C-terminalCaaX motif, including members of the RHO family, by catalyzingcarboxymethylation after prenylation. To characterize the effect ofp53 family members on transcription we generated reporters containingthe ICMT promoter. We found that ICMT expression is regulatedby complex interactions between p53 family members. Weextended the characterization by deletion mapping and chromatinchIP. Our results also showed that ICMT enhances human tumorcell clonogenic potential in vitro and tumor formation in vivo in nudemice. By using three dimensional cultures we found that ICMT isable to disrupt epithelial architecture, suggesting a role in the acquisitionof aggressive traits. The analysis of public databases alsosupports our findings on the role of ICMT as an enhancer of tumorprogression and on the link with the p53 pathway. Collectively, our data shows that ICMT deregulation cooperates with the acquisitionof aggressive phenotypes and suggests that the interplay with thep53 family may affect tumor progression.