Abstract
Overexpression of the MYC oncogene is a key feature of many human malignancies including Burkitt lymphoma. While MYC is widely regarded to be a promising therapeutic target, a clinically effective MYC inhibitor is still elusive. Here, we report an alternative strategy, targeting MYC indirectly through inhibition of the HSP90 machinery. We found that inhibition of HSP90 function reduces MYC expression in human Burkitt lymphoma through suppression of MYC transcription and destabilization of MYC protein, thereby diminishing the proliferation of tumor cells. Consistently, treatment of Burkitt lymphoma cell lines with HSP90 inhibitors (17-AAG or 17-DMAG) was accompanied by downregulation of canonical MYC target genes. Combination treatment with 17-DMAG and the proteasome inhibitor, MG-132, led to accumulation of MYC protein, indicating that upon HSP90 inhibition, MYC is degraded by the proteasome. Using co-immunoprecipitation, we furthermore demonstrated a direct interaction between MYC and HSP90, indicating that MYC is an HSP90 client protein in Burkitt lymphoma. Together, we report here the use of HSP90 inhibitors as an alternative approach to target the MYC oncogene and its network in Burkitt lymphoma.
Highlights
IntroductionThe c-MYC oncogene ( referred to as MYC) is an important driver of neoplastic transformation and is implicated in the pathogenesis of a wide variety of human cancers (reviewed in [1,2])
The c-MYC oncogene is an important driver of neoplastic transformation and is implicated in the pathogenesis of a wide variety of human cancers
Show that in Burkitt lymphoma, MYC and HSP90 exist in a complex with each other, suggesting that our results show that in Burkitt lymphoma, MYC and HSP90 exist in a complex with each other, HSP90 contributes to MYC protein stability
Summary
The c-MYC oncogene ( referred to as MYC) is an important driver of neoplastic transformation and is implicated in the pathogenesis of a wide variety of human cancers (reviewed in [1,2]). The neoplastic properties of MYC depend on its ability to deregulate a large number of genes, resulting in autonomous cellular growth and proliferation, blocked differentiation, genomic destabilization, and increased angiogenesis (reviewed in [1,5,6]). Its wide implications in human cancers and the notion that tumors can be dependent on MYC expression (oncogene addiction) make MYC and its network a highly promising target for therapeutic strategies [7,8,9]. The targeted inhibition of protein-protein interactions critical for the function or stability of MYC, such as the MYC-HSP90 axis, might be a promising strategy
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