Heat shock protein 90 regulates the expression of Wilms tumor 1 protein in myeloid leukemias.
The aberrant overexpression of Wilms tumor 1 (WT1) in myeloid leukemia plays an important role in blast cell survival and resistance to chemotherapy. High expression of WT1 is also associated with relapse and shortened disease-free survival in patients. However, the mechanisms by which WT1 expression is regulated in leukemia remain unclear. Here, we report that heat shock protein 90 (Hsp90), which plays a critical role in the folding and maturation of several oncogenic proteins, associates with WT1 protein and stabilizes its expression. Pharmacologic inhibition of Hsp90 resulted in ubiquitination and subsequent proteasome-dependant degradation of WT1. RNAi-mediated silencing of WT1 reduced the survival of leukemia cells and increased the sensitivity of these cells to chemotherapy and Hsp90 inhibition. Furthermore, Hsp90 inhibitors 17-AAG [17-(allylamino)-17-demethoxygeldanamycin] and STA-9090 significantly reduced the growth of myeloid leukemia xenografts in vivo and effectively down-regulated the expression of WT1 and its downstream target proteins, c-Myc and Bcl-2. Collectively, our studies identify WT1 as a novel Hsp90 client and support the crucial role for the WT1-Hsp90 interaction in maintaining leukemia cell survival. These findings have significant implications for developing effective therapies for myeloid leukemias and offer a strategy to inhibit the oncogenic functions of WT1 by clinically available Hsp90 inhibitors.
Bansal
Hima
H
Cancer Therapy and Research Center at The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA. bansals@uthscsa.edu
Bansal
Sanjay
S
Rao
Manjeet
M
Foley
Kevin P
KP
Sang
Jim
J
Proia
David A
DA
Blackman
Ronald K
RK
Ying
Weiwen
W
Barsoum
James
J
Baer
Maria R
MR
Kelly
Kevin
K
Swords
Ronan
R
Tomlinson
Gail E
GE
Battiwalla
Minoo
M
Giles
Francis J
FJ
Lee
Kelvin P
KP
Padmanabhan
Swaminathan
S
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D020868:Gene Silencing; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology / Q000627:therapeutic use; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs; D017434:Protein Structure, Tertiary; D014230:Triazoles / Q000627:therapeutic use; D025721:WT1 Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C533237:STA 9090; D014230:Triazoles; D025721:WT1 Proteins; C112765:tanespimycin; D005047:Etoposide; D046988:Proteasome Endopeptidase Complex