Identification of mixed lineage leukemia 1(MLL1) protein as a coactivator of heat shock factor 1(HSF1) protein in response to heat shock protein 90 (HSP90) inhibition.
Heat shock protein 90 (HSP90) inhibition inhibits cancer cell proliferation through depleting client oncoproteins and shutting down multiple oncogenic pathways. Therefore, it is an attractive strategy for targeting human cancers. Several HSP90 inhibitors, including AUY922 and STA9090, show promising effects in clinical trials. However, the efficacy of HSP90 inhibitors may be limited by heat shock factor 1 (HSF1)-mediated feedback mechanisms. Here, we identify, through an siRNA screen, that the histone H3 lysine 4 methyltransferase MLL1 functions as a coactivator of HSF1 in response to HSP90 inhibition. MLL1 is recruited to the promoters of HSF1 target genes and regulates their expression in response to HSP90 inhibition. In addition, a striking combination effect is observed when MLL1 depletion is combined with HSP90 inhibition in various human cancer cell lines and tumor models. Thus, targeting MLL1 may block a HSF1-mediated feedback mechanism induced by HSP90 inhibition and provide a new avenue to enhance HSP90 inhibitor activity in human cancers.
From the Departments of Oncology.
Yaoyu
Y
Chen
From the Departments of Oncology.
Jinyun
J
Chen
the Department of Oncology, Novartis Institutes for Biomedical Research, Emeryville, California 94608.
Jianjun
J
Yu
From the Departments of Oncology.
Guizhi
G
Yang
Developmental and Molecular Pathways, and.
Emilia
E
Temple
Developmental and Molecular Pathways, and.
Fred
F
Harbinski
From the Departments of Oncology.
Hui
H
Gao
Neuroscience, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139 and.
Christopher
C
Wilson
From the Departments of Oncology.
Raymond
R
Pagliarini
From the Departments of Oncology, wenlai.zhou@novartis.com.
Wenlai
W
Zhou
D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics; D055785:Gene Knockdown Techniques; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D000076249:Heat Shock Transcription Factors; D011495:Histone-Lysine N-Methyltransferase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D051379:Mice; D051788:Myeloid-Lymphoid Leukemia Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D012118:Resorcinols / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D018841:HSP90 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; C490017:Hsf1 protein, mouse; D007555:Isoxazoles; C497422:KMT2A protein, human; D034741:RNA, Small Interfering; D012118:Resorcinols; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse
Anticancer Drug; Heat Shock Factor 1 (HSF1); Heat Shock Protein 90 (HSP90); Tumor Cell Biology; Tumor Therapy