RESUMO
The prostate cancer (PCa) risk-associated SNP rs11672691 is positively associated with aggressive disease at diagnosis. We showed that rs11672691 maps to the promoter of a short isoform of long noncoding RNA PCAT19 (PCAT19-short), which is in the third intron of the long isoform (PCAT19-long). The risk variant is associated with decreased and increased levels of PCAT19-short and PCAT19-long, respectively. Mechanistically, the risk SNP region is bifunctional with both promoter and enhancer activity. The risk variants of rs11672691 and its LD SNP rs887391 decrease binding of transcription factors NKX3.1 and YY1 to the promoter of PCAT19-short, resulting in weaker promoter but stronger enhancer activity that subsequently activates PCAT19-long. PCAT19-long interacts with HNRNPAB to activate a subset of cell-cycle genes associated with PCa progression, thereby promoting PCa tumor growth and metastasis. Taken together, these findings reveal a risk SNP-mediated promoter-enhancer switching mechanism underlying both initiation and progression of aggressive PCa.
Assuntos
Neoplasias da Próstata/genética , RNA Longo não Codificante/genética , Alelos , Linhagem Celular Tumoral , Elementos Facilitadores Genéticos/genética , Regulação Neoplásica da Expressão Gênica/genética , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas/genética , Ligação Proteica , Isoformas de RNA/genética , Fatores de Risco , Fatores de Transcrição/metabolismo , Fator de Transcrição YY1/metabolismoRESUMO
Genome-wide association studies (GWAS) have identified rs11672691 at 19q13 associated with aggressive prostate cancer (PCa). Here, we independently confirmed the finding in a cohort of 2,738 PCa patients and discovered the biological mechanism underlying this association. We found an association of the aggressive PCa-associated allele G of rs11672691 with elevated transcript levels of two biologically plausible candidate genes, PCAT19 and CEACAM21, implicated in PCa cell growth and tumor progression. Mechanistically, rs11672691 resides in an enhancer element and alters the binding site of HOXA2, a novel oncogenic transcription factor with prognostic potential in PCa. Remarkably, CRISPR/Cas9-mediated single-nucleotide editing showed the direct effect of rs11672691 on PCAT19 and CEACAM21 expression and PCa cellular aggressive phenotype. Clinical data demonstrated synergistic effects of rs11672691 genotype and PCAT19/CEACAM21 gene expression on PCa prognosis. These results provide a plausible mechanism for rs11672691 associated with aggressive PCa and thus lay the ground work for translating this finding to the clinic.
Assuntos
Neoplasias da Próstata/genética , RNA Longo não Codificante/genética , RNA não Traduzido/genética , Adulto , Alelos , Linhagem Celular Tumoral , Cromossomos Humanos Par 19/genética , Estudos de Coortes , Regulação Neoplásica da Expressão Gênica/genética , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Genótipo , Proteínas de Homeodomínio , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , PrognósticoRESUMO
The 19q13 allele rs11672691 has been reproducibly found in association with aggressive form of prostate cancer, yet the underlying mechanism remains totally unknown. We have recently uncovered a mechanism by which rs11672691 influenced a novel oncogenic regulatory circuit, including HOXA2, PCAT19 and CEACAM21, thereby contributing to prostate cancer aggressiveness.