Abstract A05: Retrotransposon-derived RNAs in regulating cancer-related alternative splicing

Abstract

Abstract Cancer features uncontrollable growth of transformed or dedifferentiated cells. The prevalent treatment options include surgery, chemotherapy, radiation therapy, targeted therapy and transplantation. In particular, chemotherapy is designed to suppress cell growth, cause cell death and prevent cancer spread. However, the drug often kills healthy cells indiscriminately and becomes ineffective in the initially responsive patients who are then faced with an even more devastating situation. It has been suggested that there is a reciprocal feedback loop between pre-mRNA alternative splicing and chemotherapy-mediated DNA damage, hence we have investigated the potential role of pre-mRNA alternative splicing in causing resistance to chemotherapy, especially the platinum-based drug, cisplatin. In this study, we examined the expression of SR protein-specific kinases (SRPKs) and their post-translational modification in normal and cisplatin-treated Hela and MCF7 cells. While the expression of SRPK1 and SRPK2 were initially downregulated by cisplatin, the acetylated forms of these proteins were actually enhanced dramatically. Furthermore, in the established resistant cell lines, their expression was restored. The loss-of-function experiments using the siRNA knockdown, acetylation inhibitor and HAT-deficient TIP60 suggested that the acetylated SRPKs could confer the cisplatin resistance to the cancer cells by increasing the expression of those pro-growth proteins and isoforms, such as Myc, Bcl-2, Bcl-XL and CCND1b. Remarkably, in the treated and resistant cancer cells, we observed the induced expression of Alu repeats, a large family of retrotransposons with over a million copies in the human genome. These retrotransposon-derived RNAs are associated with the downstream factors of SRPKs, SR proteins. Depletion of the Alu transcripts would re-sensitize the resistant cells to cisplatin. In particular, we observed that the induced expression of Alu RNAs was required for the generation of those pro-growth proteins, possibly through interacting and synergizing with the SR proteins. Hence, the study provides novel insights into the drug resistance mechanism and will help to develop new ways of targeting retrotransposon RNAs to overcome this haunting problem in cancer treatment. Citation Format: Zhihong Zhou, Cheng Wang, Qidong Hu. Retrotransposon-derived RNAs in regulating cancer-related alternative splicing. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr A05.