Genomic and functional regulation of trib1 contributes to prostate cancer pathogenesis

Resumen

Prostate cancer (PCa) is the most frequent neoplasm and the second worldwide. Multiple key drivers of pathogenesis have been well studied, among which the oncogene c-MYC and the tumour suppressor PTEN show remarkable relevance. c-MYC gene is located on the chromosome 8q24, a region that is frequently amplified in PCa, encompassing tens of genes. However, the relevance of other genes that are co-amplified with c-MYC has not been sufficiently addressed. In this study, we aimed at identifying relevant PCa genes within the c-MYC-containing amplicon. To this end, we employed a comprehensive panel of in silico, in vitro and in vivo strategies and identified Tribbles homolog 1 (TRIB1), a member of a family of pseudokinases, as a candidate gene that contributes to PCa pathogenesis under the influence of c-MYC amplicon. Analysis of publicly available genomic and transcriptomic data revealed that TRIB1 is among the most highly expressed genes within c-MYC amplicon in PCa. Molecular analysis of the regulation of TRIB1 revealed that beyond its upregulation through amplification, this gene is also under tight transcriptional control by the PTEN-c-MYC axis, thus explaining its robust overexpression in PCa. Further characterization of the cellular phenotype resulting from TRIB1 perturbation demonstrated that alterations in this gene are inconsequential for PCa cells in vitro in cell autonomous assays. We evaluated the contribution of the pseudokinase to PCa pathogenesis in vivo through the generation of a tissue-specific conditional transgenic mouse model. Strikingly, elevation of Trib1 levels in combination with heterozygous deletion of Pten elicited PCa, together with changes in the tumour microenvironment. Overall, our work describes a novel double- layered control of TRIB1 by c-MYC and provides formal demonstration of the contribution of this pseudokinase to PCa initiation.