Epigenetic and oncogenic regulation of SLC16A7 (MCT2) results in protein over-expression, impacting on signalling and cellular phenotypes in prostate cancer


Autoria(s): Pertega-Gomes, N.; Vizcaino, J.; Felisbino, S.; Warren, A.; Shaw, G.; Kay, J.; Whitaker, H.; Lynch, A.; Fryer, L.; Neal, D.; Massie, C.
Data(s)

26/07/2016

26/07/2016

28/08/2015

Resumo

Monocarboxylate Transporter 2 (MCT2) is a major pyruvate transporter encoded by the SLC16A7 gene. Recent studies pointed to a consistent overexpression of MCT2 in prostate cancer (PCa) suggesting MCT2 as a putative biomarker and molecular target. Despite the importance of this observation the mechanisms involved in MCT2 regulation are unknown. Through an integrative analysis we have discovered that selective demethylation of an internal SLC16A7/MCT2 promoter is a recurrent event in independent PCa cohorts. This demethylation is associated with expression of isoforms differing only in 5'-UTR translational control motifs, providing one contributing mechanism for MCT2 protein overexpression in PCa. Genes co-expressed with SLC16A7/MCT2 also clustered in oncogenic-related pathways and effectors of these signalling pathways were found to bind at the SLC16A7/MCT2 gene locus. Finally, MCT2 knock-down attenuated the growth of PCa cells. The present study unveils an unexpected epigenetic regulation of SLC16A7/MCT2 isoforms and identifies a link between SLC16A7/MCT2, Androgen Receptor (AR), ETS-related gene (ERG) and other oncogenic pathways in PCa. These results underscore the importance of combining data from epigenetic, transcriptomic and protein level changes to allow more comprehensive insights into the mechanisms underlying protein expression, that in our case provide additional weight to MCT2 as a candidate biomarker and molecular target in PCa.

Felisbino S. received a fellowship from the Sao Paulo Research Foundation (FAPESP) ref. 2013/08830-2 and 2013/06802-1. Anne Y Warren research time funded by: Cambridge Biomedical Research Centre

Identificador

Oncotarget. 2015 Aug 28;6(25):21675-84

1949-2553

http://hdl.handle.net/10400.16/1977

10.18632/oncotarget.4328

Idioma(s)

eng

Publicador

Impact Journals

Relação

http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=4328&pubmed-linkout=1

Direitos

openAccess

Palavras-Chave #5' Untranslated Regions #Amino Acid Motifs #Cohort Studies #Humans #Immunohistochemistry #Male #Microscopy, Confocal #Monocarboxylic Acid Transporters #Neoplasm Metastasis #Phenotype #Prostatic Neoplasms #Protein Biosynthesis #RNA, Small Interfering #Receptors, Androgen #Signal Transduction #Trans-Activators #Epigenesis, Genetic #Gene Expression Regulation, Neoplastic
Tipo

article