Sci Adv: Wang Zefeng's team discovers a novel length-dependent splicing disorder widespread in cancer

More than 90% of the genes in the human genome need to undergo alternative splicing, and misregulation of splicing can lead to a variety of human diseases, especially cancer
.
There is increasing evidence that abnormal RNA splicing is closely related to human cancer, and widespread splicing dysregulation is one of the molecular hallmarks of cancer
.
Therefore, systematically studying the abnormal regulation of alternative splicing in cancer will provide new ideas for cancer treatment
.

On August 17, 2022, the research team of Wang Zefeng from the Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences published a research paper entitled: A widespread length dependent Splicing regulation in cancer in Science Advances, a sub-journal of Science
.

This study uncovers a novel length-dependent alternative splicing regulation pattern in cancer
.

The study first identified aberrantly spliced ​​exons in cancer by analyzing large-scale cancer transcriptome data in the TCGA database, and found that the lengths of abnormally spliced ​​exons in cancer tend to be shorter, and these short exons Exons are more likely to be skipped in cancer
.

A total of 494 cancer-associated short exons (CASE) were identified in this study and further in-depth studies were conducted
.
The research team developed a random forest model for cancer prediction using CASE splicing, which can make accurate predictions on cancer samples with an AUC of around 0.
9
.
In addition, this study also proposes a method to calculate the risk factor using CASE splicing to predict the prognosis of cancer patients, which has good prediction results in the TCGA dataset and other independent cancer datasets
.

In terms of mechanism, this study proposes two mechanisms that affect CASE splicing
.
First, aberrant transcription in cancer may have an effect on splicing, since the rapid growth and proliferation of cancer cells in cancer requires a faster transcription process
.
By analyzing alternative splicing in cell lines with different transcription elongation rates, the research team found that short exons are more sensitive to changes in speed and more susceptible to exon skipping perturbed by changes in transcription speed
.
The effects of transcription on splicing are broadly nonselective, and this study further found that specific short exons skipping in cancer are regulated by splicing factors
.
By analyzing the relevant omics data of a large number of RNA-binding proteins (RBPs) in the ENCODE database, the research team established the direct regulatory network of RBPs on CASE splicing, and identified multiple RBPs that regulate CASE splicing, including RBFOX2, AQR, U2AF2 and PTBP1 et al
.

A.
Workflow for the identification of cancer-associated splicing events based on 18 cancers in the TCGA database
.
B.
Length distribution map of all human exons and aberrantly spliced ​​exons in each cancer type
.
C.
AUC values ​​for each cancer type using splicing to build a random forest model
.
D.
Kaplan-Meier curves of cancer patients grouped based on CASE-assessed risk factors
.

Researcher Wang Zefeng from Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences and Professor Wang Yang from Cancer Stem Cell Research Institute of Dalian Medical University are the co-corresponding authors of the paper, and Dr.
Zhang Sirui from Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences is the first author of the paper
.
This work has been supported by the National Key R&D Program of the Ministry of Science and Technology, the National Natural Science Foundation of China and other scientific research projects
.

Original source:

SIRUI ZHANG, et al.
A widespread length-dependent splicing dysregulation in cancer.
SCIENCE ADVANCES, 17 Aug 2022, Vol 8, Issue 33.