ID1 and ID3 regulate the self-renewal capacity of human colon cancer-initiating cells through p21

Cancer Cell. 2012 Jun 12;21(6):777-92. doi: 10.1016/j.ccr.2012.04.036.

Abstract

There is increasing evidence that some cancers are hierarchically organized, sustained by a relatively rare population of cancer-initiating cells (C-ICs). Although the capacity to initiate tumors upon serial transplantation is a hallmark of all C-ICs, little is known about the genes that control this process. Here, we establish that ID1 and ID3 function together to govern colon cancer-initiating cell (CC-IC) self-renewal through cell-cycle restriction driven by the cell-cycle inhibitor p21. Regulation of p21 by ID1 and ID3 is a central mechanism preventing the accumulation of excess DNA damage and subsequent functional exhaustion of CC-ICs. Additionally, silencing of ID1 and ID3 increases sensitivity of CC-ICs to the chemotherapeutic agent oxaliplatin, linking tumor initiation function with chemotherapy resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Blotting, Western
  • Cell Cycle / drug effects
  • Cell Cycle / genetics
  • Cell Proliferation / drug effects
  • Colonic Neoplasms / drug therapy
  • Colonic Neoplasms / genetics*
  • Colonic Neoplasms / pathology
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics*
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Inhibitor of Differentiation Protein 1 / genetics*
  • Inhibitor of Differentiation Protein 1 / metabolism
  • Inhibitor of Differentiation Proteins / genetics*
  • Inhibitor of Differentiation Proteins / metabolism
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Microscopy, Confocal
  • Neoplasm Proteins / genetics*
  • Neoplasm Proteins / metabolism
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology
  • Organoplatinum Compounds / pharmacology
  • Oxaliplatin
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • Spheroids, Cellular / drug effects
  • Spheroids, Cellular / metabolism
  • Spheroids, Cellular / pathology
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • ID1 protein, human
  • Inhibitor of Differentiation Protein 1
  • Inhibitor of Differentiation Proteins
  • Neoplasm Proteins
  • Organoplatinum Compounds
  • Oxaliplatin
  • ID3 protein, human