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An mRNA processing pathway suppresses metastasis by governing translational control from the nucleus

View ORCID ProfileAlbertas Navickas, View ORCID ProfileHosseinali Asgharian, Juliane Winkler, Lisa Fish, Kristle Garcia, Daniel Markett, Martin Dodel, Bruce Culbertson, Sohit Miglani, Tanvi Joshi, Phi Nguyen, Steven Zhang, Nicholas Stevers, Hun-Way Hwang, Faraz Mardakheh, Andrei Goga, View ORCID ProfileHani Goodarzi
doi: https://doi.org/10.1101/2021.10.04.463118
Albertas Navickas
1Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA
2Department of Urology, University of California, San Francisco, San Francisco, CA, USA
3Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
4Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, USA
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  • ORCID record for Albertas Navickas
Hosseinali Asgharian
1Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA
2Department of Urology, University of California, San Francisco, San Francisco, CA, USA
3Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
4Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, USA
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Juliane Winkler
5Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA, USA
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Lisa Fish
1Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA
2Department of Urology, University of California, San Francisco, San Francisco, CA, USA
3Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
4Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, USA
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Kristle Garcia
1Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA
2Department of Urology, University of California, San Francisco, San Francisco, CA, USA
3Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
4Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, USA
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Daniel Markett
1Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA
2Department of Urology, University of California, San Francisco, San Francisco, CA, USA
3Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
4Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, USA
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Martin Dodel
6Centre for Cancer Cell and Molecular Biology, Barts Cancer Institute, Queen Mary University of London, London, UK
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Bruce Culbertson
1Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA
2Department of Urology, University of California, San Francisco, San Francisco, CA, USA
3Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
4Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, USA
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Sohit Miglani
1Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA
2Department of Urology, University of California, San Francisco, San Francisco, CA, USA
3Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
4Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, USA
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Tanvi Joshi
1Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA
2Department of Urology, University of California, San Francisco, San Francisco, CA, USA
3Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
4Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, USA
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Phi Nguyen
1Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA
2Department of Urology, University of California, San Francisco, San Francisco, CA, USA
3Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
4Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, USA
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Steven Zhang
1Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA
2Department of Urology, University of California, San Francisco, San Francisco, CA, USA
3Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
4Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, USA
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Nicholas Stevers
1Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA
2Department of Urology, University of California, San Francisco, San Francisco, CA, USA
3Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
4Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, USA
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Hun-Way Hwang
7Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA
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Faraz Mardakheh
6Centre for Cancer Cell and Molecular Biology, Barts Cancer Institute, Queen Mary University of London, London, UK
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Andrei Goga
3Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
5Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA, USA
8Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
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Hani Goodarzi
1Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA
2Department of Urology, University of California, San Francisco, San Francisco, CA, USA
3Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
4Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, USA
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  • For correspondence: hani.goodarzi@ucsf.edu
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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. 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 Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted October 05, 2021.
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An mRNA processing pathway suppresses metastasis by governing translational control from the nucleus
Albertas Navickas, Hosseinali Asgharian, Juliane Winkler, Lisa Fish, Kristle Garcia, Daniel Markett, Martin Dodel, Bruce Culbertson, Sohit Miglani, Tanvi Joshi, Phi Nguyen, Steven Zhang, Nicholas Stevers, Hun-Way Hwang, Faraz Mardakheh, Andrei Goga, Hani Goodarzi
bioRxiv 2021.10.04.463118; doi: https://doi.org/10.1101/2021.10.04.463118
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An mRNA processing pathway suppresses metastasis by governing translational control from the nucleus
Albertas Navickas, Hosseinali Asgharian, Juliane Winkler, Lisa Fish, Kristle Garcia, Daniel Markett, Martin Dodel, Bruce Culbertson, Sohit Miglani, Tanvi Joshi, Phi Nguyen, Steven Zhang, Nicholas Stevers, Hun-Way Hwang, Faraz Mardakheh, Andrei Goga, Hani Goodarzi
bioRxiv 2021.10.04.463118; doi: https://doi.org/10.1101/2021.10.04.463118

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