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 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.
Campbell Family Institute, Ontario Cancer Institute, Princess Margaret Hospital, University Health Network, Toronto, Ontario M5G 1L7, Canada. cobrien@uhnres.utoronto.ca
Catherine A
CA
O'Brien
Antonija
A
Kreso
Paul
P
Ryan
Karin G
KG
Hermans
Lianne
L
Gibson
Yadong
Y
Wang
Andrew
A
Tsatsanis
Steven
S
Gallinger
John E
JE
Dick
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics* / Q000378:metabolism; D051796:Inhibitor of Differentiation Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D018613:Microscopy, Confocal; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C497453:ID1 protein, human; D051798:Inhibitor of Differentiation Protein 1; D051796:Inhibitor of Differentiation Proteins; D009363:Neoplasm Proteins; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; C075640:ID3 protein, human