PACE4 Undergoes an Oncogenic Alternative Splicing Switch in Cancer.
Cancer Res
; 77(24): 6863-6879, 2017 12 15.
Article
em En
| MEDLINE
| ID: mdl-28993410
ABSTRACT
Inhibition of PACE4, a proprotein convertase that is overexpressed in prostate cancer, has been shown to block cancer progression in an androgen-independent manner. However, the basis for its overexpression and its growth-inhibitory effects are mitigated and uncertain. Here, we report that PACE4 pre-mRNA undergoes DNA methylation-sensitive alternative splicing of its terminal exon 3' untranslated region, generating an oncogenic, C-terminally modified isoform (PACE4-altCT). We found this isoform to be strongly expressed in prostate cancer cells, where it displayed an enhanced autoactivating process and a distinct intracellular routing that prevented its extracellular secretion. Together, these events led to a dramatic increase in processing of the progrowth differentiation factor pro-GDF15 as the first PACE4 substrate to be identified in prostate cancer. We detected robust expression of PACE4-altCT in other cancer types, suggesting that an oncogenic switch for this proenzyme may offer a therapeutic target not only in advanced prostate cancer but perhaps also more broadly in human cancer. Cancer Res; 77(24); 6863-79. ©2017 AACR.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Oncogenes
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Serina Endopeptidases
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Genes de Troca
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Processamento Alternativo
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Pró-Proteína Convertases
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Neoplasias
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
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Male
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article