Chemical catalyst manipulating cancer epigenome and transcription

Post-translational modification (PTM) of histones dynamically regulates gene transcription and is closely related to cancer development. Altering the epigenome is thus a promising strategy for cancer chemotherapy. However, there have been no methods to artificially introduce physiologically relevant histone PTMs and their transcription profile without genetic engineering in living cells. Here we report a cell-permeable histone acetylation catalyst, BAHA-LANA-PEG-CPP44, enabling cancer epigenome manipulation. The catalyst selectively entered leukemia cells, bound to chromatin, and selectively acetylated H2BK120 of endogenous histones in a short reaction time. The catalytic histone acetylation attenuated chromatin binding of negative elongation factor E (NELFE), an RNA polymerase II regulatory factor, and changed the transcription profile in leukemia cells. The in-cell chemical catalysis slowed proliferation of leukemia cells and reduced their tumorigenic potential in mice. As this approach requires no genetic engineering and is orthogonal to canonical epigenetic drugs, it may represent a new modality of cancer chemotherapy.