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Alternative polyadenylation is a determinant of oncogenic Ras function
Aishwarya Subramanian1, Mathew Hall2, Huayun Hou3
1Developmental and Stem Cell Biology Program, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
Science Advances
|December 17, 2021
Summary
Alternative polyadenylation, regulated by CFIM-1, impacts Ras oncogene function in development and cancer. Its disruption affects cell migration and epithelial-to-mesenchymal transition, highlighting a conserved role in cancer progression.
Area of Science:
- Molecular Biology
- Developmental Biology
- Cancer Research
Background:
- Alternative polyadenylation (APA) of mRNA plays crucial roles in biological development and cancer, though its precise functions remain unclear.
- Activating mutations in the Ras oncogene are key drivers in numerous human cancers.
- The Ras pathway is a critical signaling pathway involved in cell growth, differentiation, and survival.
Purpose of the Study:
- To investigate the role of alternative polyadenylation machinery in the context of oncogenic Ras signaling.
- To identify novel regulators of Ras function through genetic screening in Caenorhabditis elegans.
- To explore the functional consequences of altered APA in cancer cells with Ras mutations.
Main Methods:
- Conducted a genetic screen in Caenorhabditis elegans to identify enhancers of activated Ras (let-60).
- Utilized gene ablation in C. elegans and gene depletion in human cancer cells to study the function of cfim-1/CFIm25.
- Performed functional analysis of conserved transcripts affected by APA, including studies on vulva development and cell migration.
Main Results:
- Identified cfim-1, a subunit of the APA machinery, as an enhancer of let-60/Ras gain-of-function in C. elegans.
- Depletion of human CFIm25 in KRAS-mutant cancer cells promoted migration and epithelial-to-mesenchymal transition.
- Observed biased poly(A) tail placement to proximal sites in conserved transcripts in cfim-1 mutants and CFIm25-depleted cells.
- Identified mrp-5/ABCC1 as a novel regulator of C. elegans vulva development and human cell migration via alternative 3′ untranslated region (3′UTR) usage.
Conclusions:
- Alternative polyadenylation, mediated by CFIM-1/CFIm25, plays a conserved role in regulating oncogenic Ras function.
- Disruption of APA impacts key cellular processes such as cell migration and epithelial-to-mesenchymal transition, relevant to cancer progression.
- APA represents a potential therapeutic target for cancers driven by Ras pathway mutations.
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