Genomic and Functional Regulation of TRIB1 Contributes to Prostate Cancer Pathogenesis

© 2020 by the authors.
Prostate cancer is the most frequent malignancy in European men and the second worldwide. One of the major oncogenic events in this disease includes amplification of the transcription factor cMYC. Amplification of this oncogene in chromosome 8q24 occurs concomitantly with the copy number increase in a subset of neighboring genes and regulatory elements, but their contribution to disease pathogenesis is poorly understood. Here we show that TRIB1 is among the most robustly upregulated coding genes within the 8q24 amplicon in prostate cancer. Moreover, we demonstrate that TRIB1 amplification and overexpression are frequent in this tumor type. Importantly, we find that, parallel to its amplification, TRIB1 transcription is controlled by cMYC. Mouse modeling and functional analysis revealed that aberrant TRIB1 expression is causal to prostate cancer pathogenesis. In sum, we provide unprecedented evidence for the regulation and function of TRIB1 in prostate cancer.
We are grateful to the Carracedo lab for valuable input, to Ana M. Aransay and F. Elortza for technical advice. P.S. was funded by the European Training Networks Project (H2020-MSCA-ITN-308 2016 721532). V.T. is funded by Fundación Vasca de Innovación e Investigación Sanitarias, BIOEF (BIO15/CA/052), the AECC J.P. Bizkaia, the Basque Department of Health (2016111109) and the MICINN RTI2018-097267-B-I00. A. Macchia was funded by a FPI predoctoral fellowship from MICINN (PRE2018-083607). EB is funded by the MICINN (BFU2016-76872-R (FEDER/EU), PID2019-108112RB-I00, Severo Ochoa Excellence Accreditation SEV-2016-0644 and Excellence Networks SAF2017-90794-REDT). The work of A. Carracedo is supported by the Basque Department of Industry, Tourism and Trade (Elkartek), the department of education (IKERTALDE IT1106-16) and health (RIS3), the BBVA foundation and the MICINN (SAF2016-79381-R (FEDER/EU; PID2019-108787RB-I00) Severo Ochoa Excellence Accreditation SEV-2016-0644 and Excellence Networks SAF2016-81975-REDT and RED2018-102769-T), European Training Networks Project (H2020-MSCA-ITN-308 2016 721532), the AECC (IDEAS175CARR, GCTRA18006CARR), La Caixa Foundation (ID 100010434), under the agreement LCF/PR/HR17/ and the European Research Council (Starting Grant 336343, Consolidator Grant 819242). CIBERONC was co-funded with FEDER funds and funded by ISCIII.