Keratin 19 binds and regulates cytoplasmic HNRNPK mRNA targets in triple-negative breast cancer.
Breast Cancer
Gene expression
HNRNPK
Keratin 19
PAR-CLIP
Proliferation
RNA binding protein
RNA-protein interaction
p53
Journal
BMC molecular and cell biology
ISSN: 2661-8850
Titre abrégé: BMC Mol Cell Biol
Pays: England
ID NLM: 101741148
Informations de publication
Date de publication:
17 Aug 2023
17 Aug 2023
Historique:
received:
28
12
2022
accepted:
09
08
2023
medline:
21
8
2023
pubmed:
18
8
2023
entrez:
17
8
2023
Statut:
epublish
Résumé
Heterogeneous 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. Here 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). This 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.
Sections du résumé
BACKGROUND
BACKGROUND
Heterogeneous 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.
RESULTS
RESULTS
Here 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).
CONCLUSIONS
CONCLUSIONS
This 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.
Identifiants
pubmed: 37592256
doi: 10.1186/s12860-023-00488-z
pii: 10.1186/s12860-023-00488-z
pmc: PMC10433649
doi:
Substances chimiques
RNA, Messenger
0
Heterogeneous-Nuclear Ribonucleoprotein K
0
Keratin-19
0
3' Untranslated Regions
0
HNRNPK protein, human
146410-60-8
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
26Subventions
Organisme : NIAMS NIH HHS
ID : R01 AR044232
Pays : United States
Organisme : NCI NIH HHS
ID : R15 CA213071
Pays : United States
Organisme : NCI NIH HHS
ID : R15CA213071
Pays : United States
Informations de copyright
© 2023. BioMed Central Ltd., part of Springer Nature.
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