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
  • 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. [email protected].
  • 12. Southern California Research Center for ALPD and Cirrhosis, Los Angeles, CA, 90033, USA. [email protected].
  • # 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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