An mRNA processing pathway suppresses metastasis by governing translational control from the nucleus
Abstract
Cancer cells often co-opt post-transcriptional regulatory mechanisms to achieve pathologic expression of gene networks that drive metastasis. Translational control is a major regulatory hub in oncogenesis; however, its effects on cancer progression remain poorly understood. Here, to address this, we used ribosome profiling to compare genome-wide translation efficiencies of poorly and highly metastatic breast cancer cells and patient-derived xenografts. We developed dedicated regression-based methods to analyse ribosome profiling and alternative polyadenylation data, and identified heterogeneous nuclear ribonucleoprotein C (HNRNPC) as a translational controller of a specific mRNA regulon. We found that HNRNPC is downregulated in highly metastatic cells, which causes HNRNPC-bound mRNAs to undergo 3′ untranslated region lengthening and, subsequently, translational repression. We showed that modulating HNRNPC expression impacts the metastatic capacity of breast cancer cells in xenograft mouse models. In addition, the reduced expression of HNRNPC and its regulon is associated with the worse prognosis in breast cancer patient cohorts.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- May 08, 2023
- Source ID
- 10.1038/s41556-023-01141-9
Entities
People
- Albertas Navickas
- Andrei Goga
- Bruce Culbertson
- Daniel Markett
- Faraz Khosravi Mardakheh
- Hani Goodarzi
- Hosseinali Asgharian
- Hun-Way Hwang
- Juliane Winkler
- Keyi Yin
- Kristle Garcia
- Lisa Fish
- Martin Dodel
- Nicholas Stevers
- Phi Nguyen
- Sohit Miglani
- Steven Zhang
- Tanvi Joshi
Organizations
- American Cancer Society
- Boehringer Ingelheim Fonds
- Congressionally Directed Medical Research Programs
- European Molecular Biology Organization
- Howard Hughes Medical Institute
- Medical Research Council
- National Institutes of Health