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

Hye Yeon Choi, Hifzur R. Siddique, Mengmei Zheng, Yi Kou, Da-Wei Yeh, Tatsuya Machida, Chia-Lin Chen, Dinesh Babu Uthaya Kumar, Vasu Punj, Peleg Winer, Alejandro Pita, Linda Sher, Stanley M. Tahara, Ratna B. Ray, Chengyu Liang, Lin Chen, Hidekazu Tsukamoto and Keigo Machida ()
Additional contact information
Hye Yeon Choi: University of Southern California
Hifzur R. Siddique: University of Southern California
Mengmei Zheng: University of Southern California
Yi Kou: University of Southern California
Da-Wei Yeh: University of Southern California
Tatsuya Machida: University of Southern California
Chia-Lin Chen: University of Southern California
Dinesh Babu Uthaya Kumar: University of Southern California
Vasu Punj: University of Southern California
Peleg Winer: University of Southern California
Alejandro Pita: University of Southern California
Linda Sher: University of Southern California
Stanley M. Tahara: University of Southern California
Ratna B. Ray: Saint Louis University
Chengyu Liang: University of Southern California
Lin Chen: University of Southern California
Hidekazu Tsukamoto: University of Southern California
Keigo Machida: University of Southern California

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: 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.

Date: 2020
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-020-16616-8 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16616-8

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-020-16616-8

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().