Keratin 19 binds and regulates cytoplasmic HNRNPK mRNA targets in triple-negative breast cancer

BMC Molecular and Cell Biology

Research

Ahmed Elgerbi¹  Byung Min Chung¹  Pooja Sharma¹  Sarah Alsharif¹  Arwa Fallatah²  Pierre A. Coulombe³  Markus Hafner⁴  Alexis Jacob⁴  Dimitrios G. Anastasakis⁴  Xiantao Wang⁴  Amirhossein Manzourolajdad⁵ 

[1]Department of Biology, The Catholic University of America, Washington, DC, United States of America

[2]Department of Biology, The Catholic University of America, Washington, DC, United States of America

[3]RNA Molecular Biology Laboratory, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD, United States of America

[4]Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, United States of America

[5]Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI, United States of America

[6]RNA Molecular Biology Laboratory, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD, United States of America

[7]RNA Molecular Biology Laboratory, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD, United States of America

[8]Department of Computer Science, Colgate University, Hamilton, NY, United States of America

关键词: Keratin 19;    HNRNPK;    PAR-CLIP;    Gene expression;    Breast Cancer;    p53;    Proliferation;    RNA binding protein;    RNA-protein interaction;   

DOI  :  10.1186/s12860-023-00488-z

 received in 2022-12-28, accepted in 2023-08-09,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundHeterogeneous nuclear ribonucleoprotein K (HNRNPK) regulates pre-mRNA processing and long non-coding RNA localization in the nucleus. It was previously shown that shuttling of HNRNPK to the cytoplasm promotes cell proliferation and cancer metastasis. However, the mechanism of HNRNPK cytoplasmic localization, its cytoplasmic RNA ligands, and impact on post-transcriptional gene regulation remain uncharacterized.ResultsHere we show that the intermediate filament protein Keratin 19 (K19) directly interacts with HNRNPK and sequesters it in the cytoplasm. Correspondingly, in K19 knockout breast cancer cells, HNRNPK does not localize in the cytoplasm, resulting in reduced cell proliferation. We comprehensively mapped HNRNPK binding sites on mRNAs and showed that, in the cytoplasm, K19-mediated HNRNPK-retention increases the abundance of target mRNAs bound to the 3’ untranslated region (3’UTR) at the expected cytidine-rich (C-rich) sequence elements. Furthermore, these mRNAs protected by HNRNPK in the cytoplasm are typically involved in cancer progression and include the p53 signaling pathway that is dysregulated upon HNRNPK knockdown (HNRNPK KD) or K19 knockout (KRT19 KO).ConclusionsThis study identifies how a cytoskeletal protein can directly regulate gene expression by controlling the subcellular localization of RNA-binding proteins to support pathways involved in cancer progression.

【 授权许可】

CC BY   
© BioMed Central Ltd., part of Springer Nature 2023

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