Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 297, Issue 2, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.jbc.2021.100996
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Funding
- National Natural Science Foundation of China [81672582, 31771521]
- Natural Science Foundation of Jiangsu Province for Distinguished Young Scholars [BK20160013]
- Natural Science Foundation of Jiangsu Province [BE2016718]
- Top Talent of Innovative Research Team of Jiangsu Province
- Six Talent Peak Project from Government of Jiangsu Province [2015-SWYY-019, 2016-SWYY-011]
- Start-up Scientific Research Fund for the Returned Oversea Scholars from Chinese Ministry of Education [P30 CA006927]
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The study found that HSP90 inhibition effectively suppresses the growth of MCL cells, with 12-hour exposure almost as efficient as continuous exposure. By transcriptome analysis and functional studies, several genes were consistently downregulated in MCL cells after transient ganetespib treatment, which are involved in DNA replication and repair.
Mantle 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 h was almost as efficient as continuous exposure, and treatment with ganetespib for 12 h efficiently inhibited growth and induced G1 cell cycle arrest and apoptosis of MCL cells. Transcriptome analysis complemented by functional studies was performed to define critical MCL signaling pathways that are exceptionally sensitive to HSP90 inhibition and vital to cell fate. Six genes (cell division cycle 6, cell division cycle 45, minichromosome maintenance 4, minichromosome maintenance 7, RecQ-mediated genome instability 2, and DNA primase polypeptide 1) 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 six 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.
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