Abstract
Although inhibition of the androgen–androgen receptor (AR) axis effectively represses the growth of prostate cancer, most of all cases eventually become castration-resistant prostate cancers (CRPCs). Enhancement of the expression of AR and its variants along with the downstream signals is important for disease progression. AR-V7, a constitutive active form of AR, is generated as a result of RNA splicing. RNA splicing creates multiple transcript variants from one pre-messenger RNA (mRNA) by removing introns/exons to allow mRNA translation. The molecular mechanisms leading to marked increases of AR and generation of AR-V7 have been unclear. However, recent papers highlighted the roles of RNA splicing factors which promote AR expression and production of variants. Notably, a broad range of splicing components were aberrantly regulated in CRPC tissues. Interestingly, expression of various spliceosome genes is enhanced by RNA-binding protein splicing factor proline- and glutamine-rich (PSF/SFPQ), leading to changes in the expression of AR transcript variants. Moreover, inhibition of several splicing factors repressed tumor growth in vivo. Altered expression of splicing factors is correlated to biochemical recurrence in prostate cancer patients. Thus, these findings suggest that splicing factors would be a potential therapeutic target. This review focuses on the emerging roles of splicing factors in prostate cancer progression and AR signaling.
Highlights
Dysregulation of gene expression is a well-known feature of cancer cells [1]
These mutations were found predominantly in both SF3B1 and U2AF1, which participate in core spliceosomal components that recognize the 3’ SS and serine/arginine rich splicing factor 2 (SRSF2), an SR protein [44,45,46,47,48,49]
Another report showed that the recruitment of U2 small nuclear RNA auxiliary factor 2 (U2AF2) to the 3’ splice site of androgen receptor (AR)-V7 with SRSF1 was enhanced by ADT to produce increased expression of AR-V7 [60]
Summary
Dysregulation of gene expression is a well-known feature of cancer cells [1]. RNA (mRNA) splicing to remove introns from precursor messenger RNA (pre-mRNA) is a critical step in the post-transcriptional regulation of gene expression [2]. Recent genomic sequencing studies identified that the mutation and aberrant expression of splicing factors are important mechanisms to generate the diversity of gene functions required for cancer progression. Several important reports have demonstrated that the androgen receptor (AR) splicing pathway is a key driver for prostate cancer progression [10,11,12,13]. Biomolecules 2019, 9, 131; doi:10.3390/biom9040131 www.mdpi.com/journal/biomolecules as AR overexpression, intra-tumoral androgen synthesis, induced expression of AR co-regulators, and alternative AR activation by cytokines and growth factors [16,17,18]. A number of AR-Vs have been identified in prostate cancer cell lines and xenografts, AR-V7 is the most commonly expressed AR-V in CRPC tissues [19]
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