Long non-coding RNA-protein interactions and butyrate sensitization of colorectal cancer cells

Ali SR, Orang AV, McKinnon RA and Michael MZ

Flinders Centre for Innovation in Cancer, Flinders University, Flinders Medical Centre, Adelaide, South Australia.

Colorectal cancer (CRC) is the second most common cause of Australian cancer related deaths. The development of CRC is associated with epigenetic alterations including altered histone acetylation patterns and dysregulated long non-coding RNA (lncRNA) expression. Butyrate, a short-chain fatty acid, produced from the fermentation of dietary fibre in our gut, has been shown to alter CRC cell behaviour through epigenetic mechanisms. Butyrate can alter CRC gene expression, including lncRNA expression, via histone deacetylase inhibition activity, resulting in decreased proliferation and increased apoptosis. lncRNAs regulate gene expression through various mechanisms including epigenetic modifications, lncRNA-miRNA, lncRNA-mRNA, lncRNA-protein interactions and their ability to produce regulatory ncRNAs, such as miRNAs. lncRNAs have been shown to regulate cell growth and apoptotic pathways in CRC. The effect of exposing CRC cells to the anti-tumorigenic molecule, butyrate, in combination with lncRNA knockdown has yet to be investigated. High throughput functional screens were used to systematically identify oncogenic lncRNAs, which when knocked down resulted in the sensitization of CRC cells to butyrate (enhanced anti-proliferative and pro-apoptotic effects). Knockdown of some lncRNAs resulted in enhanced apoptosis in the presence of butyrate. Pathway and network analyses assisted in identification of predicted key lncRNA-protein interactions involved in apoptosis. Further investigation of lncRNA knockdown and their protein interactors in the context of butyrate is required. Identification of oncogenic lncRNAs, and protein interactors, with the ability to sensitise CRC cells to butyrate when suppressed, may reveal the potential chemo-preventive or therapeutic value of these biological molecules.