Celastrol inhibits lung cancer growth by triggering histone acetylation and acting synergically with HDAC inhibitors

Alterations in histone modification have been linked to cancer development and progression. Celastrol, a Chinese herbal compound, shows potent anti-tumor effects through multiple signaling pathways. However, the involvement of histone modifications in this process has not yet been illustrated. In this study, barcode sequencing of a eukaryotic genome-wide deletion library revealed that histone modifications, especially histone acetylation associated with the NuA4 histone acetyltransferase complex, were involved in the anti-proliferation actions of celastrol. The essential roles of histone modification were verified by celastrol sensitivity tests in cells lacking specific genes, such as genes encoding the subunits of the NuA4 and Swrl complex. The combination of celastrol and histone deacetylase inhibitors (HDACi), rather than the combination of celastrol and histone acetyltransferase inhibitors, synergistically suppressed cancer cell proliferation. In addition to upregulating H4K16 acetylation (H4K16ac), celastrol regulates H3K4 tri-methylation and H3S10 phosphorylation. Celastrol treatment significantly enhanced the suppressive effects of HDACi on lung cancer cell allografts in mice, with significant H4K16ac upregulation, indicating that a combination of celastrol and HDACi is a potential novel therapeutic approach for patients with lung cancer.

Automated summary

Alterations in histone modification have been shown to be related to cancer development and progression. Celastrol, a Chinese herbal compound, exhibits potent anti-tumor effects through multiple signaling pathways. This study demonstrates that histone modifications, especially histone acetylation associated with the NuA4 histone acetyltransferase complex, are involved in the anti-proliferation actions of celastrol. Combination therapy with celastrol and histone deacetylase inhibitors (HDACi) synergistically suppresses cancer cell proliferation. The results suggest that the combination of celastrol and HDACi could be a potential novel therapeutic approach for lung cancer patients.