Targeting the MYC interaction network in B-cell lymphoma via histone deacetylase 6 inhibition

Area of Science:

• Oncology
• Molecular Biology
• Epigenetics

Background:

• Overexpression of the MYC oncogene drives lymphomas and predicts poor prognosis.
• Targeting MYC directly is a significant therapeutic challenge in cancer treatment.

Purpose of the Study:

• To investigate the therapeutic potential of inhibiting histone deacetylase 6 (HDAC6) in MYC-driven B-cell lymphomas.
• To elucidate the molecular mechanism by which HDAC6 inhibition affects MYC levels and lymphomagenesis.

Main Methods:

• Utilized Marbostat-100 (M-100), an HDAC6 inhibitor, in a mouse model of MYC-induced aggressive B-cell lymphoma.
• Analyzed the effects of M-100 on MYC protein levels, tubulin acetylation, and apoptosis in cancer cells.
• Identified DNAJA3 as a key interactor in the acetylation-dependent regulation of MYC turnover.

Main Results:

• M-100 treatment significantly reduced oncogenic MYC levels and prevented lymphomagenesis in vivo.
• HDAC6 inhibition led to tubulin hyperacetylation, impairing MYC nuclear import and promoting its proteasomal degradation.
• M-100 selectively targeted MYC-overexpressing B-cell lymphoma cells, inducing massive apoptosis without affecting non-tumor cells.
• DNAJA3 was identified as a mediator of MYC degradation through interaction with hyperacetylated tubulin.

Conclusions:

• HDAC6 inhibition represents a promising therapeutic strategy for MYC-dependent B-cell lymphomas.
• The mechanism involves modulating tubulin acetylation to control MYC stability and turnover.
• M-100 demonstrates high specificity and efficacy against MYC-driven lymphomas.