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Interactive web portal details the extent of splicing events in noncoding sequences

Interactive web portal details the extent of splicing events in noncoding sequences

An online tool reveals the extent of gene-restructuring events in noncoding sequences.

An interactive web portal developed by scientists at KAUST offers a platform for cancer researchers to interrogate how RNA splicing in noncoding parts of genes fuels the growth of different types of tumors.

The new resource, named SpUR (short for Splicing in Untranslated Regions) and freely available online, details more than 1,000 splicing events found frequently in cancers in noncoding regions of mRNA located just downstream of protein-coding stop signals. The sites and expression levels of these events are catalogued and visualized for nearly 8,000 samples across 10 cancer types and corresponding normal tissues.

With the tool, independent research teams can now further probe the role of individual splice events in cancer development and progression.

These events could become candidates to study RNA dysregulations in cancer for academic researchers. Or they could serve as a primary source for the development of RNA-based anti-cancer drugs.”


Xin Gao, acting associate director of the Computational Bioscience Research Center and deputy director of the Smart Health Initiative at KAUST

Computer scientist Gao, together with postdoc Bin Zhang and research engineer Adil Salhi, created the SpUR database in collaboration with researchers at the Cancer Science Institute of Singapore.

The research showed that splicing in downstream sequences of a gene (known as 3′ untranslated regions, or 3′ UTRs) is pervasive in cancers, especially in genes linked to tumor aggression. Consequently, patients whose cancers harbor more of these gene-restructuring events tend to have poorer survival outcomes.

As a proof of principle, the researchers designed splice-switching agents known as antisense oligonucleotides (ASOs) that could block this splicing process in 3′ UTRs. When administered to liver cancer cells, these drugs helped repress tumor growth. And since the same kinds of splicing events are “ubiquitously expressed across different cancer types,” Gao notes, this type of therapeutic strategy “could be helpful to develop broad-spectrum anti-cancer drugs.”

One potential target:CTNNB1, which is a gene that provides instructions for making a protein called beta-catenin. Drug companies have long tried to target beta-catenin, given its central role in many cancer-signaling pathways, but with only limited success. The study from Gao and his collaborators showed that splicing in the 3′ UTR ofCTNNB1is widespread across cancers of the liver, breast, colon, kidney, lung and other organs, and that a spliced variant is the predominant driver of tumor progression.

In a mouse model of liver cancer, blocking this splicing resulted in complete tumor regression. An ASO therapy directed atCTNNB1splicing could therefore have broad utility in patients, and, as Gao points out, it is not likely to be the only one.

Source:

Journal reference:

Chan, J.J., et al. (2022) Pan-cancer, pervasive upregulation of 3’UTR splicing drives tumorigenesis. Nature Cell Biology. doi.org/10.1038/s41556-022-00913-z.

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Ask SAM: Are there any shredding events coming up?

Ask SAM: Are there any shredding events coming up?

Mount Tabor United Methodist Church, 3543 Robinhood Road, Winston Salem, will have a shredding event from 9 a.m. to noon April 23. They will accept monetary donations to benefit food programs serving children in Forsyth County and other missions of the United Methodist Women. Make checks payable to Mt. Tabor UMC-Circle 5. For more information, call the church 336-765-5561 or go to www.mttaborumc.org.

New Philadelphia Moravian Church, 4440 Country Club Road, Winston-Salem, will have a document shred from 9 a.m. to noon April 23. The cost is $5 per box. Enter from Kilpatrick Street. They will unload. You do not have to get out of your vehicle. The shredding is sponsored by the Advent Class. Proceeds will benefit outreach ministries of the Moravian Church. For more information, call 336-972-0494 or visit www.newphilly.org.

Fries Memorial Moravian Church, 251 N. Hawthorne Road, Winston Salem, will have a community shred day from 9 a.m. to noon April 30. Shamrock Shredding will be shredding documents on-site in the church parking lot. Donations of $5 per file box or bag are requested. Paper only, no plastic or non-paper trash will be accepted. Proceeds will benefit local youth and family ministries.

Hopewell Moravian Church will have two shredding events at the Griffith Volunteer Fire Department, 5190 Peters Creek Parkway, Winston-Salem. The first will be 10 a.m. to 1 p.m. April 30. The second will be 10 a.m. to 1 p.m. June 25. A $5 per bag or box donation is suggested.