ID1 and ID3 Regulate the Self-Renewal Capacity of Human Colon Cancer-Initiating Cells through p21

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 thi...

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Bibliographic Details
Published in:	Cancer cell 2012-06, Vol.21 (6), p.777-792
Main Authors:	O'Brien, Catherine A., Kreso, Antonija, Ryan, Paul, Hermans, Karin G., Gibson, Lianne, Wang, Yadong, Tsatsanis, Andrew, Gallinger, Steven, Dick, John E.
Format:	Article
Language:	eng
Subjects:	Animals Antineoplastic Agents - pharmacology Blotting, Western Cancer Cell Cycle - drug effects Cell Cycle - genetics Cell Proliferation - drug effects Chemotherapy Colon Colonic Neoplasms - drug therapy Colonic Neoplasms - genetics Colonic Neoplasms - pathology Cyclin-Dependent Kinase Inhibitor p21 - genetics Cyclin-Dependent Kinase Inhibitor p21 - metabolism DNA damage 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 Reverse Transcriptase Polymerase Chain Reaction RNA Interference Spheroids, Cellular - drug effects Spheroids, Cellular - metabolism Spheroids, Cellular - pathology Tumor Cells, Cultured Tumors Xenograft Model Antitumor Assays
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Summary:	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. ► ID1 and ID3 together govern the maintenance of colon cancer-initiating cells ► ID1 and ID3 orchestrate their effect through the cell-cycle inhibitor, p21 ► ID1 and ID3 expression reduces sensitivity to the chemotherapeutic drug, oxaliplatin
ISSN:	1535-6108 1878-3686