BEX2 suppresses mitochondrial activity and is required for dormant cancer stem cell maintenance in intrahepatic cholangiocarcinoma

Sci Rep. 2020 Dec 9;10(1):21592. doi: 10.1038/s41598-020-78539-0.


Cancer stem cells (CSCs) define a subpopulation of cancer cells that are resistant to therapy. However, little is known of how CSC characteristics are regulated. We previously showed that dormant cancer stem cells are enriched with a CD274low fraction of cholangiocarcinoma cells. Here we found that BEX2 was highly expressed in CD274low cells, and that BEX2 knockdown decreased the tumorigenicity and G0 phase of cholangiocarcinoma cells. BEX2 was found to be expressed predominantly in G0 phase and starvation induced the USF2 transcriptional factor, which induced BEX2 transcription. Comprehensive screening of BEX2 binding proteins identified E3 ubiquitin ligase complex proteins, FEM1B and CUL2, and a mitochondrial protein TUFM, and further demonstrated that knockdown of BEX2 or TUFM increased mitochondria-related oxygen consumption and decreased tumorigenicity in cholangiocarcinoma cells. These results suggest that BEX2 is essential for maintaining dormant cancer stem cells through the suppression of mitochondrial activity in cholangiocarcinoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bile Duct Neoplasms / genetics
  • Bile Duct Neoplasms / metabolism*
  • Bile Duct Neoplasms / pathology
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Cholangiocarcinoma / genetics
  • Cholangiocarcinoma / metabolism*
  • Cholangiocarcinoma / pathology
  • Cullin Proteins / genetics
  • Cullin Proteins / metabolism
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Mitochondria / genetics
  • Mitochondria / metabolism*
  • Mitochondria / pathology
  • Neoplastic Stem Cells / metabolism*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Oxygen Consumption / physiology


  • BEX2 protein, human
  • CUL2 protein, human
  • Carrier Proteins
  • Cell Cycle Proteins
  • Cullin Proteins
  • FEM1B protein, human
  • Nerve Tissue Proteins