­Histone deacetylase enzyme activity is not the universal anti-cancer target of HDAC inhibitors [RNA-seq_MC38]

Here, we performed unbiased bioinformatics analysis and found that genetic variants or expression levels of HDACs do not correlate with the carcinogenesis of most cancer types and do not predict cancer patient survival. Whole-genome CRISPR library screens did not identify HDACs as genes affecting cellular responses to HDIs such as SAHA or MS-275.

Overexpression of dominant-negative, catalytically inactive Class I HDACs (HDAC1, 2, 3, and 8) caused a similar degree of histone hyperacetylation as Class I-specific HDI FK228 in cancer cell lines without similar anti-cancer effects, transcriptomic changes, or cellular responses to FK228. The anti-cancer effects of FK228 can be further dissociated from the histone hyperacetylation in an in-situ liver cancer mouse model.