PRMT5: Learning From Development To Target Splicing In Cancer Therapy

Ernesto Guccione, Ph.D., Institute of Molecular and Cell Biology (IMCB) 61 Biopolis Drive, Singapore 138673

21 July 2014
Versione stampabile

July 21 2014
Edificio Povo 2, via Sommarive nr. 9, Povo (TN)

3.00 p.m.

Deregulated expression of the MYC (c-Myc) transcription factor occurs in the majority of human cancers and correlates with high proliferation, reprogrammed cellular metabolism and poor prognosis. MYC binds to all active promoters within a cell, although with different binding affinities, and modulates their transcription, both positively and negatively. We identify PRMT5, an arginine methyltransferase, which is essential for snRNP biogenesis, as a key factor able to promote survival and proliferation of Eμ-Myc driven tumors. In vivo, its deletion markedly reduces the tumorigenicity of xenografted lymphoma cells, reducing disease burden and increasing the survival of recipient mice. Notably, PRMT5 is indispensible in cycling cells, proportionally to the rate of proliferation, but is not in resting cells. Our data indicate that the core snRNP assembly machinery, including PRMT5, functions downstream of MYC as a rate-limiting regulator of cell proliferation and transformation. Targeting the splicing machinery via PRMT5 inhibition with small molecule inhibitors could be a viable therapeutic strategy, specifically in MYC-driven cancers.