title: Epigenetic and oncogenic regulation of SLC16A7 (MCT2) results in protein over-expression, impacting on signalling and cellular phenotypes in prostate cancer.
abstract: 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.
authors.affiliation: Uro-oncology Research Group, CRUK Cambridge Institute, Cambridge, UK.
authors.forename: Nelma
authors.initials: N
authors.lastname: Pertega-Gomes
authors.affiliation: Department of Pathology, Centro Hospitalar do Porto, Porto, Portugal.
authors.forename: Jose R
authors.initials: JR
authors.lastname: Vizcaino
authors.affiliation: Department of Morphology, Institute of Biosciences, Sao Paulo State University (UNESP), Sao Paulo, Brazil.
authors.forename: Sergio
authors.initials: S
authors.lastname: Felisbino
authors.affiliation: Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
authors.forename: Anne Y
authors.initials: AY
authors.lastname: Warren
authors.affiliation: Uro-oncology Research Group, CRUK Cambridge Institute, Cambridge, UK.
authors.forename: Greg
authors.initials: G
authors.lastname: Shaw
authors.affiliation: Uro-oncology Research Group, CRUK Cambridge Institute, Cambridge, UK.|Molecular Diagnostics and Therapeutics Group, University College London, London, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Kay
authors.affiliation: Uro-oncology Research Group, CRUK Cambridge Institute, Cambridge, UK.|Molecular Diagnostics and Therapeutics Group, University College London, London, UK.
authors.forename: Hayley
authors.initials: H
authors.lastname: Whitaker
authors.affiliation: Statistics and Computational Biology Group, CRUK Cambridge Institute, Cambridge, UK.
authors.forename: Andy G
authors.initials: AG
authors.lastname: Lynch
authors.affiliation: Uro-oncology Research Group, CRUK Cambridge Institute, Cambridge, UK.
authors.forename: Lee
authors.initials: L
authors.lastname: Fryer
authors.affiliation: Uro-oncology Research Group, CRUK Cambridge Institute, Cambridge, UK.|Department of Urology, University of Cambridge, Department of Oncology, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: David E
authors.initials: DE
authors.lastname: Neal
authors.affiliation: Uro-oncology Research Group, CRUK Cambridge Institute, Cambridge, UK.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Massie
mesh_terms: D020121:5' Untranslated Regions; D020816:Amino Acid Motifs; D015331:Cohort Studies; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D018613:Microscopy, Confocal; D027501:Monocarboxylic Acid Transporters / Q000235:genetics* / Q000378:metabolism*; D009362:Neoplasm Metastasis; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000378:metabolism*; D014176:Protein Biosynthesis; D034741:RNA, Small Interfering / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D000071230:Transcriptional Regulator ERG
chemical_list: D020121:5' Untranslated Regions; C410798:AR protein, human; C072312:ERG protein, human; D027501:Monocarboxylic Acid Transporters; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; C490427:SLC16A7 protein, human; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG
keywords: castrate resistant disease; malignant phenotype; monocarboxylate transporter 2; prostate cancer