Targeting CDK9: a promising therapeutic opportunity in prostate cancer
- Muhammed H Rahaman*,
- Malika Kumarasiri*,
- Laychiluh B Mekonnen,
- Mingfeng Yu,
- Sarah Diab,
- Hugo Albrecht,
- Robert W Milne and
- Shudong Wang⇑
- Centre for Drug Discovery and Development, Sansom Institute for Health Research and School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia
- Correspondence should be addressed to S Wang; Email: shudong.wang{at}unisa.edu.au
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Figure 1
Regulation of transcription by CDK9. Inhibitory complex consisting of LARP7, HEXIM, 7SK and ncRNA gets activated upon interaction with BRD4 and SEC, releasing P-TEFb. Activated P-TEFb is recruited to the initiation complex by interacting with TFs and phosphorylates CTD Ser2, NELF and DSIF for productive elongation.
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Figure 2
Schematic representation of the androgen receptor (gene and protein) major domains and phosphorylation sites. Exon1 codes for NTD; exons 2 and 3 code for DBD; exon 4 for hinge; and exons 5, 6, 7 and 8 for LBD. All the AR splice variants share similarity with the NTD and DBD. Introduction of cryptic exons due to exon skipping or alternative splicing results in unique regions.
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Figure 3
CDK9-AR-mediated pathway in PCa. Under normal conditions, AR is activated and dimerizes upon androgen induction and mediates transcriptional activity by binding to the ARE. In androgen dependent CRPC, reactivation of AR occurs due to AR gene amplification, which makes it hypersensitive to low level of androgen or due to persistent/ectopic production of androgen by the prostate cells. Inhibition of CDK9 phosphorylating both the AR and RNAPII can put on a break on the AR overactivity and expression of prostate-specific genes.
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Figure 4Proposed mechanism of androgen independency in CRPC. (A) Mutated AR binding to alternative steroids or antiandrogen and AR-Vs act through androgen independent pathway of CRPC. (B) Higher association with other TFs like MYC, NF-кB and STAT family members affects AR recruitment to DNA and/or regulates AR target gene expression. (C) In bypass pathway, overexpression of anti-apoptotic Bcl-2 family of proteins prevents prostate cells from death despite of ADT.
- © 2016 Society for Endocrinology
