Our 3rd prize winner is:
Isabella is in her final year at Imperial College London where she is studying Biochemistry. Throughout her time as an undergraduate she has become particularly interested in cancer research and spent last summer working for Cancer Research UK. Congratulations, Isabella! Read her entry below:
Long non-coding RNA and its “lnc” to Prostate Cancer
Despite much research, prostate cancer still represents a major cause of morbidity and mortality in males, warranting a new avenue of investigation. In parallel, this decade, long non-coding RNAs (lncRNAs) have risen from obscurity and are now known to be major regulators of gene expression. LncRNAs have been identified that regulate tumour suppressor genes, oncogenes and the androgen receptor signalling pathway; three important processes that can drive the progression of prostate cancer (PCa) if misregulated. In this essay I will discuss two recently identified prostate cancer-associated lncRNAs: HOTAIR and SChLAP1.
It has been known that PCa is an androgen driven disease since the discovery by Huggins and Hughes in 1941. Androgen-depletion therapy is the primary treatment for advanced PCa(1). However, after 2-3 years the cancer progresses to castration-resistant prostate cancer (CRPC) due to AR hyperactivity(2). The AR is a nuclear receptor that translocates into the nucleus after binding an androgenic hormone where it acts as a transcription factor, regulating a large repertoire of genes key to the behaviour and fate of prostate cancer cells(3). HOTAIR, is an androgen-repressed lncRNA that is significantly upregulated in CRPC cell lines(4). Subsequent experiments demonstrated that HOTAIR binds the N-terminal domain of the AR protein, which prevents the E3 ubiquitin ligase, MDM2, from binding. This prevents AR degradation thereby increasing the stability of AR. As a result, HOTAIR induces androgen-independent AR activation, a major cause of CRPC(4).
SChLAP1 is an intergenic lncRNA transcribed from a gene desert located on chromosome 2(5). Studies have reported that SChLAP is one of the best prognostic indicators of lethal prostate cancer and can be used clinically as a urine-based biomarker(5). SChLAP1 co-immunoprecipitates with a component of the SWI/SNF complex and prevents it binding to DNA(5). SWI/SNF is a conglomerate that remodels chromatin especially at promoters to increase access to DNA for transcription(6). This explains why SChLAP1 overexpression reduces the expression of tumour-suppressor genes.
Research into the lncRNAs involved in PCa has only just commenced and already studies have shown that they play key roles in disease pathogenesis and progression. The mechanisms by which lncRNAs control chromatin is becoming a hot topic in genomics due to the potential of lncRNA, due to its unique properties, to affect chromatin in ways that proteins cannot. The lncRNAs discussed have distinct expression patterns that can serve as biomarkers for PCa diagnosis and prognosis as well as potential drug targets. While lncRNAs are already being used as diagnostic biomarkers, a more thorough understanding of their functions and mechanisms in PCa pathology is required before therapeutics are developed. This may require advances in the experimental techniques used to study lncRNAs to overcome the reproducibility issues that have plagued lncRNA research.
1 Perlmutter and Lepor (2007). Androgen Deprivation Therapy in the Treatment of Advanced Prostate Cancer. Rev Urol. 9 Suppl 1: S3–8.
2 Levina E et al. (2015) Identification of novel genes that regulate androgen receptor signaling and growth of androgen-deprived prostate cancer cells. Oncotarget. 6 (13088–13104).
3 Chandrasekar, T et al. (2015). Mechanisms of resistance in castration-resistant prostate cancer (CRPC). Translational Andrology and Urology, 4(3), 365–380.
4 Zhang, A et al. (2015). LncRNA HOTAIR Enhances the Androgen-Receptor-Mediated Transcriptional Program and Drives Castration-Resistant Prostate Cancer. Cell Reports, 13(1), 209–221.
5 Prensner, J et al. (2013). The long noncoding RNA SChLAP1 promotes aggressive prostate cancer and antagonizes the SWI/SNF complex. Nature Genetics, 45(11), 1392-1398.
6 Archacki, R. et al. (2016). Arabidopsis SWI/SNF chromatin remodeling complex binds both promoters and terminators to regulate gene expression. Nucleic Acids Research.