Blocking the spliceosome delays the progression of lymphoma in mice
A widespread cancer-causing protein called MYC promotes the growth of tumor cells in part by ensuring that RNA transcripts are properly spliced, according to latest work from A*STAR researchers1. Drugs that block parts of the cell’s splicing machinery may provide a new way to halt the proliferation of MYC-driven cancers.
“Cells overexpressing the oncogene MYC will be more sensitive to inhibition of the splicing machinery,” says Ernesto Guccione, from the A*STAR Institute of Molecular and Cell Biology, who led the research. “Targeting the core components of the splicing machinery may be a novel Achilles’ heel to therapeutically target MYC-driven tumors.”
The MYC oncoprotein is a central driver in the majority of human cancers. MYC binds to active regulatory elements in the genome and broadly amplifies gene expression, leading to rampant cell growth. This process, however, is not random or indiscriminate. Guccione, in collaboration with colleagues in Italy, recently showed that MYC preferentially activates distinct subsets of target genes to control cellular states2.
Following up on that observation, Guccione and his colleagues from A*STAR decided to investigate which gene sets are turned on by MYC in mouse models of lymphoma. One gene set that stood out involved components of the spliceosome, the molecular complex that helps prepare messenger RNA (mRNA) transcripts for protein production by removing noncoding segments called introns.
These genes include PRMT5, which codes for a key enzyme that ensures proper maturation of the spliceosomal complex. PRMT5 and others help assemble the proteins that form the spliceosome. Guccione’s team showed that mice with only one functional copy of PRMT5 — instead of the usual two — develop lymphoma more slowly.
PRMT5 depletion led to a range of splicing defects linked to the retarded tumor growth. And drug-like molecules called antisense oligonucleotides (which disrupt proper splicing) also reduced the viability of cancer cells taken from mice with lymphoma. Together, the results suggest that splicing-associated genes like PRMT5 are critical to MYC-driven tumor formation.
Further support for this idea came from human clinical samples. Guccione and colleagues studied samples from people with lymphoma. They found a link between MYC overexpression and the activity of spliceosome-related genes. Notably, high expression of PRMT5 correlated with worse clinical outcomes. In the laboratory, knocking out PRMT5, or another core component of the splicing machinery in human lymphoma cells lines, also reduced cell viability.
“The inhibition of PRMT5 may have potential therapeutic utility in cancer treatment,” explains Cheryl Koh, a postdoctoral fellow in Guccione’s lab and the co-first author of the new study.
The A*STAR-affiliated researchers contributing to this research are from the Institute of Molecular and Cell Biology, the Institute of High Performance Computing and the Bioinformatics Institute.
Koh, C. M., Bezzi, M., Low, D. H. P., Ang, W. X., Teo, S. X. et al. MYC regulates the core Pre-mRNA splicing machinery as an essential step in lymphomagenesis. Nature advance online publication, 11 May 2015 (doi: 10.1038/nature14351). | article
Sabò, A., Kress, T. R., Pelizzola, M., de Pretis, S., Gorski, M. M. et al. Selective transcriptional regulation by Myc in cellular growth control and lymphomagenesis. Nature 511, 488–492 (2014). | article
At last, butterflies get a bigger, better evolutionary tree
16.02.2018 | Florida Museum of Natural History
New treatment strategies for chronic kidney disease from the animal kingdom
16.02.2018 | Veterinärmedizinische Universität Wien
Breakthrough provides a new concept of the design of molecular motors, sensors and electricity generators at nanoscale
Researchers from the Institute of Organic Chemistry and Biochemistry of the CAS (IOCB Prague), Institute of Physics of the CAS (IP CAS) and Palacký University...
For photographers and scientists, lenses are lifesavers. They reflect and refract light, making possible the imaging systems that drive discovery through the microscope and preserve history through cameras.
But today's glass-based lenses are bulky and resist miniaturization. Next-generation technologies, such as ultrathin cameras or tiny microscopes, require...
Scientists from the University of Zurich have succeeded for the first time in tracking individual stem cells and their neuronal progeny over months within the intact adult brain. This study sheds light on how new neurons are produced throughout life.
The generation of new nerve cells was once thought to taper off at the end of embryonic development. However, recent research has shown that the adult brain...
Theoretical physicists propose to use negative interference to control heat flow in quantum devices. Study published in Physical Review Letters
Quantum computer parts are sensitive and need to be cooled to very low temperatures. Their tiny size makes them particularly susceptible to a temperature...
Let’s say the armrest is broken in your vintage car. As things stand, you would need a lot of luck and persistence to find the right spare part. But in the world of Industrie 4.0 and production with batch sizes of one, you can simply scan the armrest and print it out. This is made possible by the first ever 3D scanner capable of working autonomously and in real time. The autonomous scanning system will be on display at the Hannover Messe Preview on February 6 and at the Hannover Messe proper from April 23 to 27, 2018 (Hall 6, Booth A30).
Part of the charm of vintage cars is that they stopped making them long ago, so it is special when you do see one out on the roads. If something breaks or...
15.02.2018 | Event News
13.02.2018 | Event News
12.02.2018 | Event News
16.02.2018 | Information Technology
16.02.2018 | Health and Medicine
16.02.2018 | Physics and Astronomy