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

Bartosz Mucha, Shuo Qie, Sagar Bajpai, Vincenzo Tarallo, J. Nathaniel Diehl, Frank Tedeschi, Gao Zhou, Zhaofeng Gao, Samuel Flashner, Andres J. Klein-Szanto, Hanina Hibshoosh, Shimonosono Masataka, Olga S. Chajewski, Ireneusz Majsterek, Dariusz Pytel, Maria Hatzoglou, Channing J. Der, Hiroshi Nakagawa, Adam J. Bass, Kwok-Kin Wong, Serge Y. Fuchs, Anil K. Rustgi, Eckhard Jankowsky and J. Alan Diehl ()
Additional contact information
Bartosz Mucha: Case Comprehensive Cancer Center, Case Western Reserve University
Shuo Qie: Case Comprehensive Cancer Center, Case Western Reserve University
Sagar Bajpai: Case Comprehensive Cancer Center, Case Western Reserve University
Vincenzo Tarallo: Case Comprehensive Cancer Center, Case Western Reserve University
J. Nathaniel Diehl: University of North Carolina at Chapel Hill
Frank Tedeschi: Case Comprehensive Cancer Center, Case Western Reserve University
Gao Zhou: Case Comprehensive Cancer Center, Case Western Reserve University
Zhaofeng Gao: Case Western Reserve University
Samuel Flashner: Columbia University Irving Medical Center
Andres J. Klein-Szanto: Fox Chase Cancer Center
Hanina Hibshoosh: Columbia University Irving Medical Center
Shimonosono Masataka: Columbia University Irving Medical Center
Olga S. Chajewski: Medical University of South Carolina
Ireneusz Majsterek: Medical University of Lodz
Dariusz Pytel: Medical University of South Carolina
Maria Hatzoglou: Case Western Reserve University
Channing J. Der: University of North Carolina at Chapel Hill
Hiroshi Nakagawa: Columbia University Irving Medical Center
Adam J. Bass: Columbia University Irving Medical Center
Kwok-Kin Wong: New York University
Serge Y. Fuchs: University of Pennsylvania
Anil K. Rustgi: Columbia University Irving Medical Center
Eckhard Jankowsky: Case Comprehensive Cancer Center, Case Western Reserve University
J. Alan Diehl: Case Comprehensive Cancer Center, Case Western Reserve University

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: 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 SCFFbxo4 E3 ubiquitin ligase restricts the pro-oncogenic activity of hnRNPK via K63 linked polyubiquitylation, thus limiting its ability to bind target mRNA. We identify SCFFbxo4-hnRNPK responsive mRNAs whose products regulate cellular processes including proliferation, migration, and invasion. Loss of SCFFbxo4 leads to enhanced cell invasion, migration, and tumor metastasis. C-Myc was identified as one target of SCFFbxo4-hnRNPK. Fbxo4 loss triggers hnRNPK-dependent increase in c-Myc translation, thereby contributing to tumorigenesis. Increased c-Myc positions SCFFbxo4-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.

Date: 2022
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DOI: 10.1038/s41467-022-34402-6

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