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

Abstract

Cancer 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.

DRP1: At the Crossroads of Dysregulated Mitochondrial Dynamics and Altered Cell Signaling in Cancer Cells

“…Recent studies reported that impaired mitochondrial fission resulted in impaired asymmetric division of cancer stem cells (CSC). Downregulation of YY2, the transcription factor of DRP1, was observed in liver CSC in this study …”

YY2/BUB3 Axis promotes SAC Hyperactivation and Inhibits Colorectal Cancer Progression via Regulating Chromosomal Instability

“…YY2 is a zinc‐finger protein and has been reported to have a tumor suppressive function. [ 29 , 30 , 31 , 32 ] A comparative analysis using clinical CRC tissues and corresponding normal adjacent tissues revealed a significant decrease in YY2 mRNA and protein levels in CRC tissues (Figure S3A,B , Supporting Information). Furthermore, YY2 overexpression significantly suppressed the viability and colony‐formation potential of HCT116 cells (Figure S3C,D , Supporting Information).…”

Transcriptional regulation of cancer stem cell: regulatory factors elucidation and cancer treatment strategies

“…In order to target TFs to regulate the transcription of CSCs and obtain clinical benefits, there are several methods and strategies as follows: (1) TFs gene expression; (6) Inducing ambient pressure such as metabolism, hypoxia and immune response to cause TFs inactivation (Fig. 1).…”

“…CSCs occupy a very small amount in tumor tissue, and they have similar TFs and signaling pathways compared to stem cells in healthy tissues [3,4]. One prominent hallmark of CSCs is asymmetric division, which generates more CSCs and specially-differentiated daughter cells [5,6]. Another important feature of CSCs is epithelial-mesenchymal transition (EMT), a reversible cellular process that temporarily puts epithelial cells in a quasi-mesenchymal state.…”