TY - JOUR
T1 - HSF1 drives a transcriptional program distinct from heat shock to support highly malignant human cancers
AU - Mendillo, Marc L.
AU - Santagata, Sandro
AU - Koeva, Martina
AU - Bell, George W.
AU - Hu, Rong
AU - Tamimi, Rulla M.
AU - Fraenkel, Ernest
AU - Ince, Tan A.
AU - Whitesell, Luke
AU - Lindquist, Susan
N1 - Funding Information:
We thank G. Frampton, I. Barrasa and S.Gupta for bioinformatic assistance. We thank T. Mazor, T. Volkert and the WIBR-GTC for sequencing support. We thank the Lindquist lab and T. Lee for discussion and K. Allendoerfer, B. Bevis, G. Karras, R. Shouval and K. Matlack for comments. The work was supported by the J&J COSAT focused funding program (L.W.) and the Marble Fund (S.L.). S.L. is an Investigator of the Howard Hughes Medical Institute. M.L.M. is supported by American Cancer Society New England Division-SpinOdyssey (PF-09-253-01-DMC). S.S. is supported by NIH (K08NS064168), the Brain Science Foundation and the V Foundation. Additional support was provided by GSK (WE234 EPI40307); Public Health Service Grants CA087969, and SPORE in Breast Cancer CA089393, from the NCI, NIH, Dept. of Health and Human Services. T.A.I is supported by the Breast Cancer Research Foundation, NCI (R01-CA146445-01) and DoD-CDMRP Breast Cancer Research Program (W81XWH-08-1-0282 BC-07456). T.A. Ince receivse royalty payments for WIT medium and was a consultant to Stemgent Inc. during 2008–2010. We thank the participants and staff of the NHS, and state cancer registries: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY.
PY - 2012/8/3
Y1 - 2012/8/3
N2 - Heat-Shock Factor 1 (HSF1), master regulator of the heat-shock response, facilitates malignant transformation, cancer cell survival, and proliferation in model systems. The common assumption is that these effects are mediated through regulation of heat-shock protein (HSP) expression. However, the transcriptional network that HSF1 coordinates directly in malignancy and its relationship to the heat-shock response have never been defined. By comparing cells with high and low malignant potential alongside their nontransformed counterparts, we identify an HSF1-regulated transcriptional program specific to highly malignant cells and distinct from heat shock. Cancer-specific genes in this program support oncogenic processes: cell-cycle regulation, signaling, metabolism, adhesion and translation. HSP genes are integral to this program, however, many are uniquely regulated in malignancy. This HSF1 cancer program is active in breast, colon and lung tumors isolated directly from human patients and is strongly associated with metastasis and death. Thus, HSF1 rewires the transcriptome in tumorigenesis, with prognostic and therapeutic implications.
AB - Heat-Shock Factor 1 (HSF1), master regulator of the heat-shock response, facilitates malignant transformation, cancer cell survival, and proliferation in model systems. The common assumption is that these effects are mediated through regulation of heat-shock protein (HSP) expression. However, the transcriptional network that HSF1 coordinates directly in malignancy and its relationship to the heat-shock response have never been defined. By comparing cells with high and low malignant potential alongside their nontransformed counterparts, we identify an HSF1-regulated transcriptional program specific to highly malignant cells and distinct from heat shock. Cancer-specific genes in this program support oncogenic processes: cell-cycle regulation, signaling, metabolism, adhesion and translation. HSP genes are integral to this program, however, many are uniquely regulated in malignancy. This HSF1 cancer program is active in breast, colon and lung tumors isolated directly from human patients and is strongly associated with metastasis and death. Thus, HSF1 rewires the transcriptome in tumorigenesis, with prognostic and therapeutic implications.
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U2 - 10.1016/j.cell.2012.06.031
DO - 10.1016/j.cell.2012.06.031
M3 - Article
C2 - 22863008
AN - SCOPUS:84864585171
SN - 0092-8674
VL - 150
SP - 549
EP - 562
JO - Cell
JF - Cell
IS - 3
ER -
