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PACE4 Undergoes an Oncogenic Alternative Splicing Switch in Cancer
Frédéric Couture1,2,3, Robert Sabbagh2,3, Anna Kwiatkowska1,2,3
1Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Québec, Canada.
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.
Insights
Prostate cancer cells produce a variant of PACE4 (proprotein convertase subtilisin/kexin type 4) that promotes tumor growth by altering its function and location. This PACE4 variant also increases processing of pro-GDF15, offering a potential therapeutic target.
Area of Science:
- Molecular oncology
- Cancer biology
- Biochemistry
Background:
- Proprotein convertase PACE4 is overexpressed in prostate cancer, but the mechanisms and effects are unclear.
- PACE4 inhibition can block cancer progression independently of androgens.
Purpose of the Study:
- Investigate the basis of PACE4 overexpression in prostate cancer.
- Identify the functional consequences of PACE4 alterations in cancer cells.
- Determine the role of PACE4 in prostate cancer progression.
Main Methods:
- Analysis of DNA methylation-sensitive alternative splicing of PACE4 pre-mRNA.
- Characterization of the PACE4-altCT isoform in prostate cancer cells.
- Assessment of PACE4 substrate processing, specifically pro-GDF15.
- Detection of PACE4-altCT expression in various cancer types.
Main Results:
- PACE4 pre-mRNA undergoes alternative splicing, generating an oncogenic PACE4-altCT isoform.
- PACE4-altCT is highly expressed in prostate cancer cells, exhibiting enhanced autoactivation and altered intracellular routing.
- This leads to increased processing of pro-GDF15, a novel PACE4 substrate in prostate cancer.
- PACE4-altCT is also expressed in other cancer types.
Conclusions:
- A novel oncogenic switch involving PACE4 alternative splicing and C-terminal modification drives prostate cancer progression.
- The PACE4-altCT isoform promotes tumor growth through enhanced autoactivation and increased pro-GDF15 processing.
- Targeting this PACE4 variant represents a potential therapeutic strategy for advanced prostate cancer and other human cancers.