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Cited by 23Ubiquitin and proteasome pathwaysRNA Research and SplicingCancer-related Molecular Pathways

Tumor suppressor mediated ubiquitylation of hnRNPK is a barrier to oncogenic translation

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Mucha, Bartosz, Qie, Shuo, Bajpai, Sagar, Tarallo, Vincenzo, Diehl, J. Nathaniel, Tedeschi, Frank, Zhou, Gao, Gao, Zhaofeng +16 more·2022·Nature Communications
DOI 10.1038/s41467-022-34402-6PMC PMC9633729
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Abstract

Heterogeneous Nuclear Ribonucleoprotein K (hnRNPK) is a multifunctional RNA binding protein (RBP) localized in the nucleus and the cytoplasm. Abnormal cytoplasmic enrichment observed in solid tumors often correlates with poor clinical outcome. The mechanism of cytoplasmic redistribution and ensuing functional role of cytoplasmic hnRNPK remain unclear. Here we demonstrate that the SCF Fbxo4 E3 ubiquitin ligase restricts the pro-oncogenic activity of hnRNPK via K63 linked polyubiquitylation, thus limiting its ability to bind target mRNA. We identify SCF Fbxo4-hnRNPK responsive mRNAs whose products regulate cellular processes including proliferation, migration, and invasion. Loss of SCF Fbxo4 leads to enhanced cell invasion, migration, and tumor metastasis. C-Myc was identified as one target of SCF Fbxo4-hnRNPK. Fbxo4 loss triggers hnRNPK-dependent increase in c-Myc translation, thereby contributing to tumorigenesis. Increased c-Myc positions SCF Fbxo4-hnRNPK dysregulated cancers for potential therapeutic interventions that target c-Myc-dependence. This work demonstrates an essential role for limiting cytoplasmic hnRNPK function in order to maintain translational and cellular homeostasis.

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  • HNRNPK inhibits GBM cells by inhibiting the proliferation of cancer cells.

    “HNRNPK plays an important role in inhibiting GBM cells by inhibiting the proliferation of cancer cells (31).”

    From Functional interaction between miR-505-3p and miR-21 contributes to GBM suppression (2026) · cites this paper as [31]

    The Results section (“SCFFbxo4-hnRNPK-c-Myc regulates cell proliferation”; page not provided) reports that hnRNPK expression promoted proliferation in mouse embryonic fibroblasts, while hnRNPK knockdown prevented it—the opposite of the attributed inhibitory effect. The cited passages do not report an experiment in GBM cells. (LLM, conf=0.86)

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Authors
Mucha, B., Qie, S., Bajpai, S., Tarallo, V., Diehl, J. N., Tedeschi, F., Zhou, G., Gao, Z., Flashner, S., Klein-Szanto, A. J., Hibshoosh, H., Masataka, S., Chajewski, O. S., Majsterek, I., Pytel, D., Hatzoglou, M., Der, C. J., Nakagawa, H., Bass, A. J., Wong, K.-K., Fuchs, S. Y., Rustgi, A. K., Jankowsky, E., & Diehl, J. A.
Affiliations
  • Case Comprehensive Cancer Center (US)
  • Case Western Reserve University (US)
  • Columbia University Irving Medical Center (US)
  • Medical University of South Carolina (US)
  • Medical University of Lodz (PL)
  • University of North Carolina at Chapel Hill (US)
  • NYU Langone’s Laura and Isaac Perlmutter Cancer Center (US)
  • University of Pennsylvania (US)
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2022-11-03
Volume
13
Issue
1
Pages
6614-6614
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-022-34402-6
PMC
PMC9633729
OpenAlex
W4308045418
Cited by
23
References
4
Citations by year
2026: 8 · 2025: 7 · 2024: 7 · 2023: 1
FWCI
1.31
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • U.S. Department of Health & Human Services | National Institutes of Health (R01DK53307, R01DK060596)
  • U.S. Department of Health & Human Services | NIH | National Cancer Institute (CA098101)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Keywords
hnRNP K, RNA-binding proteins, oncogenic translation, tumor suppressor, metastasis, cell migration and invasion, tumor cell proliferation
MeSH terms
Humans, Oncogenes, RNA, Messenger, RNA-Binding Proteins, Heterogeneous-Nuclear Ribonucleoprotein K, Ubiquitination, Carcinogenesis

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