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HSP90 inhibition downregulates DNA replication and repair genes via E2F1 repression
J Biol Chem. 2021 Jul 21;297(2) :100996
PMID: 34302809 PMCID: PMC8363837 URL: https://www.ncbi.nlm.nih.gov/pubmed/34302809
AbstractMantle cell lymphoma (MCL) is an especially aggressive and highly heterogeneous mature B cell lymphoma. Heat shock protein 90 (HSP90) is considered an attractive therapeutic target in a variety of cancers, including MCL, but no HSP90 inhibitors have succeeded in the clinical trials to date. Exploring fine mechanisms of HSP90 inhibition in cancer cells may shed light on novel therapeutic strategies. Here we found that HSP90 knockdown and continuous inhibition with ganetespib inhibited growth of MCL cells in vitro and in vivo. To our surprise, transient exposure over 12 hours was almost as efficient as continuous exposure, and treatment with ganetespib for 12 hours efficiently inhibited growth and induced G1 cell cycle arrest and apoptosis of MCL cells. Transcriptome analysis complemented by functional studies were performed to define critical MCL signaling pathways that are exceptionally sensitive to HSP90 inhibition and vital to cell fate. Six genes (CDC6, CDC45, MCM4, MCM7, RMI2, and PRIM1) involved in DNA replication and repair were identified as consistently downregulated in three MCL cell lines after transient ganetespib treatment. E2F1, an important transcription factor essential for cell cycle progression, was identified as a ganetespib target mediating transcriptional downregulation of these 6 genes, and its stability was also demonstrated to be maintained by HSP90. This study identifies E2F1 as a novel client protein of HSP90 that is very sensitive and worthy of targeting, and also finds that HSP90 inhibitors may be useful in combination therapies for MCL.
Notes1083-351x Liu, Hanqing Lu, Ziwen Shi, Xiaofeng Liu, Lanlan Zhang, Peishan Golemis, Erica A Tu, Zhigang Journal Article United States J Biol Chem. 2021 Jul 21:100996. doi: 10.1016/j.jbc.2021.100996.