YY2‐DRP1 Axis Regulates Mitochondrial Fission and Determines Cancer Stem Cell Asymmetric Division

Author:

Wei Mankun12,Nurjanah Uli12,Li Juan12,Luo Xinxin12,Hosea Rendy12,Li Yanjun12,Zeng Jianting3,Duan Wei12,Song Guanbin1,Miyagishi Makoto4,Kasim Vivi125ORCID,Wu Shourong125ORCID

Affiliation:

1. Key Laboratory of Biorheological Science and Technology Ministry of Education College of Bioengineering Chongqing University Chongqing 400044 P. R. China

2. The 111 Project Laboratory of Biomechanics and Tissue Repair College of Bioengineering Chongqing University Chongqing 400044 P. R. China

3. Department of Hepatobiliary and Pancreatic Oncology Chongqing University Cancer Hospital Chongqing University Chongqing 400030 P. R. China

4. Life Science Innovation School of Integrative and Global Majors University of Tsukuba Tsukuba Ibaraki 305‐0006 Japan

5. Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment Chongqing University Cancer Hospital Chongqing University Chongqing 400030 P. R. China

Abstract

AbstractCancer stem cells (CSCs) are associated with tumor progression, recurrence, and therapeutic resistance. To maintain their pool while promoting tumorigenesis, CSCs divide asymmetrically, producing a CSC and a highly proliferative, more differentiated transit‐amplifying cell. Exhausting the CSC pool has been proposed as an effective antitumor strategy; however, the mechanism underlying CSC division remains poorly understood, thereby largely limiting its clinical application. Here, through cross‐omics analysis, yin yang 2 (YY2) is identified as a novel negative regulator of CSC maintenance. It is shown that YY2 is downregulated in stem‐like tumor spheres formed by hepatocarcinoma cells and in liver cancer, in which its expression is negatively correlated with disease progression and poor prognosis. Furthermore, it is revealed that YY2 overexpression suppressed liver CSC asymmetric division, leading to depletion of the CSC pool and decreased tumor‐initiating capacity. Meanwhile, YY2 knock‐out in stem‐like tumor spheres caused enrichment in mitochondrial functions. Mechanistically, it is revealed that YY2 impaired mitochondrial fission, and consequently, liver CSC asymmetric division, by suppressing the transcription of dynamin‐related protein 1. These results unravel a novel regulatory mechanism of mitochondrial dynamic‐mediated CSCs asymmetric division and highlight the role of YY2 as a tumor suppressor and a therapeutic target in antitumor treatment.

Funder

National Natural Science Foundation of China

Natural Science Foundation of Chongqing

Publisher

Wiley

Subject

General Physics and Astronomy,General Engineering,Biochemistry, Genetics and Molecular Biology (miscellaneous),General Materials Science,General Chemical Engineering,Medicine (miscellaneous)

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