2. Academic Validation
  3. p53 destabilizing protein skews asymmetric division and enhances NOTCH activation to direct self-renewal of TICs

p53 destabilizing protein skews asymmetric division and enhances NOTCH activation to direct self-renewal of TICs

  • Nat Commun. 2020 Jun 17;11(1):3084. doi: 10.1038/s41467-020-16616-8.
Hye Yeon Choi # 1,  Hifzur R Siddique # 1 2,  Mengmei Zheng 1,  Yi Kou 3,  Da-Wei Yeh 1,  Tatsuya Machida 1,  Chia-Lin Chen 1,  Dinesh Babu Uthaya Kumar 1 4,  Vasu Punj 5,  Peleg Winer 1,  Alejandro Pita 6,  Linda Sher 6,  Stanley M Tahara 1,  Ratna B Ray 7,  Chengyu Liang 1,  Lin Chen 3,  Hidekazu Tsukamoto 8 9 10,  Keigo Machida 11 12
Affiliations

Affiliations

  • 1 Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA, 90033, USA.
  • 2 Section of Genetics, Department of Zoology, Aligarh Muslim University, Aligarh, 202002, India.
  • 3 Department of Chemistry and Biological Sciences, University of Southern California, Los Angeles, CA, 90089, USA.
  • 4 Department of Genetics and Genomics, and The Jackson Laboratory for Genomic Medicine, University of Connecticut Health, Farmington, 06032, CT, USA.
  • 5 Department of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
  • 6 Department of Surgery, University of Southern California, Los Angeles, CA, 90033, USA.
  • 7 Saint Louis University, St. Louis, MO, 63103, USA.
  • 8 Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
  • 9 Southern California Research Center for ALPD and Cirrhosis, Los Angeles, CA, 90033, USA.
  • 10 VA Greater Los Angeles Healthcare System, Los Angeles, 90073, CA, USA.
  • 11 Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA, 90033, USA. keigo.machida@med.usc.edu.
  • 12 Southern California Research Center for ALPD and Cirrhosis, Los Angeles, CA, 90033, USA. keigo.machida@med.usc.edu.
  • # Contributed equally.
PMID: 32555153 DOI: 10.1038/s41467-020-16616-8
Abstract

Tumor-initiating stem-like cells (TICs) are defective in maintaining asymmetric cell division and responsible for tumor recurrence. Cell-fate-determinant molecule NUMB-interacting protein (TBC1D15) is overexpressed and contributes to p53 degradation in TICs. Here we identify TBC1D15-mediated oncogenic mechanisms and tested the tumorigenic roles of TBC1D15 in vivo. We examined hepatocellular carcinoma (HCC) development in alcohol Western diet-fed hepatitis C virus NS5A Tg mice with hepatocyte-specific TBC1D15 deficiency or expression of non-phosphorylatable NUMB mutations. Liver-specific TBC1D15 deficiency or non-p-NUMB expression reduced TIC numbers and HCC development. TBC1D15-NuMA1 association impaired asymmetric division machinery by hijacking NuMA from LGN binding, thereby favoring TIC self-renewal. TBC1D15-NOTCH1 interaction activated and stabilized NOTCH1 which upregulated transcription of NANOG essential for TIC expansion. TBC1D15 activated three novel oncogenic pathways to promote self-renewal, p53 loss, and Nanog transcription in TICs. Thus, this central regulator could serve as a potential therapeutic target for treatment of HCC.

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