RT Journal Article
SR Electronic
T1 An mRNA processing pathway suppresses metastasis by governing translational control from the nucleus
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.10.04.463118
DO 10.1101/2021.10.04.463118
A1 Albertas Navickas
A1 Hosseinali Asgharian
A1 Juliane Winkler
A1 Lisa Fish
A1 Kristle Garcia
A1 Daniel Markett
A1 Martin Dodel
A1 Bruce Culbertson
A1 Sohit Miglani
A1 Tanvi Joshi
A1 Phi Nguyen
A1 Steven Zhang
A1 Nicholas Stevers
A1 Hun-Way Hwang
A1 Faraz Mardakheh
A1 Andrei Goga
A1 Hani Goodarzi
YR 2021
UL http://biorxiv.org/content/early/2021/10/05/2021.10.04.463118.abstract
AB 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. 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 novel regression-based methods to analyze ribosome profiling and alternative polyadenylation data, and identified HNRNPC as a translational controller of a specific mRNA regulon. Mechanistically, HNRNPC, in concert with PABPC4, binds near to poly(A) signals, thereby governing the alternative polyadenylation of a set of mRNAs. We found that HNRNPC and PABPC4 are downregulated in highly metastatic cells, which causes HNRNPC-bound mRNAs to undergo 3’ UTR lengthening and subsequently, translational repression. We showed that modulating HNRNPC expression impacts the metastatic capacity of breast cancer cells in xenograft mouse models. We also found that a small molecule, previously shown to induce a distal-to-proximal poly(A) site switching, counteracts the HNRNPC-PABPC4 driven deregulation of alternative polyadenylation and decreases the metastatic lung colonization by breast cancer cells in vivo.Competing Interest StatementThe authors have declared no competing interest.