The role of SIDT2 in tumour suppression
Dr Ken Pang(Primary)
Dr Tracy Putoczki(Co-supervisor)
Details of project
The discovery of regulatory RNAs has challenged long-held assumptions about the role of RNA in the cell and revolutionised our understanding of biology and disease 1.
SID-1 is an RNA transporter that enables the cell-to-cell spread of regulatory RNAs in the nematode C. elegans2, 3. SID-1 orthologs are present in all mammals and appear to have retained RNA transporter function4, but their actual physiological roles are currently unknown.
We have recently observed that one of the two mammalian SID-1 orthologs, SIDT2, is frequently downregulated in human cancers. Consistent with this observation, experiments that inhibit SIDT2 activity promote tumour growth in vivo, while experiments that enhance SIDT2 activity restrain the proliferation of cancer cells in vitro5. Taken together, these observations support the hypothesis that an important physiological role of SIDT2 is to suppress tumour formation.
The overall goal of this project is to dissect the role of SIDT2 in tumour suppression. In particular, we wish to understand how the likely RNA transport function of SIDT2 relates to its potential anti-cancer activity. This work should provide important new insights into how cancer cells grow, and will hopefully identify new targets for anti-cancer treatment.
- Taft RJ, Pang KC, Mercer TR, Dinger M, Mattick JS. Noncoding RNAs: regulators of disease. J Pathol. 2010 Jan;220(2):126-39. PMID:19882673
- Winston WM, Molodowitch C, Hunter CP. Systemic RNAi in C. elegans requires the putative transmembrane protein SID-1. Science. 2002 Mar 29;295(5564):2456-9. PMID:11834782Wolfrum C, Shi S, Jayaprakash KN, Jayaraman M, Wang G, Pandey RK, Rajeev KG, Nakayama T, Charrise K, Ndungo EM, Zimmermann T, Koteliansky V, Manoharan M, Stoffel M.
- Mechanisms and optimization of in vivo delivery of lipophilic siRNAs. Nat Biotechnol 2007.25, 1149-1157 PMID:17873866
- Brady CA, Jiang D, Mello SS, Johnson TM, Jarvis LA, Kozak MM, Kenzelmann Broz D, Basak S, Park EJ, McLaughlin ME, Karnezis AN, Attardi LD. Distinct p53 transcriptional programs dictate acute DNA-damage responses and tumor suppression. Cell. 2011 May 13;145(4):571-83. PMID: 21565614
The primary focus of our research is to understand the movement of RNAs into and between cells. We are interested in this question for several reasons.
First, a better understanding of RNA movement should help improve basic biological knowledge. For example, it was recently discovered that RNAs move between cells. This discovery has the potential to transform how we view cell-to-cell communication within our bodies, much like the seminal discovery of hormones such as insulin and cortisol in the first half of last century.
Second, knowing how RNAs enter cells has a direct bearing on the treatment of disease. For example, the discovery of RNA interference in 1998 has stimulated billions of dollars of investment in the development of RNA therapeutics. Despite this investment, not a single RNA-based drug has yet to be approved for clinical use, due largely to problems of ineffective delivery into cells. Improving our knowledge of how RNA moves into cells should help to address this issue.
To better understand RNA movement, we are studying the mammalian orthologs of SID-1, a large transmembrane protein that transports RNA across cell membranes. In the nematode C. elegans, SID-1 enables the movement of RNA interference between cells, and published evidence indicates that the mammalian SID-1 orthologs have retained their RNA transport function.
- Cell Biology