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.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Couture F,Sabbagh R,Kwiatkowska A,Desjardins R,Guay SP,Bouchard L,Day Rdoi
10.1158/0008-5472.CAN-17-1397subject
Has Abstractpub_date
2017-12-15 00:00:00pages
6863-6879issue
24eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-17-1397journal_volume
77pub_type
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