Chromatin accessibility and transcriptomic responses to HDAC inhibitors in TP53 mutated patient-derived colon cancer organoids [RNA-seq]

Here we present the generation and characterization of patient-derived organoids (PDOs) from colorectal cancer patients. Two PDOs derived from patients with TP53 mutations were tested with two different HDACIs (SAHA and NKL54). Induction of cell death, transcriptome, and chromatin accessibility changes were analyzed. HDACIs promote the upregulation of low expressed genes and suppress the expression of highly expressed genes. A similar differential effect is also observed at the level of chromatin accessibility. Only SAHA is a potent inducer of cell death. The induction of apoptosis is characterized by the upregulation of BH3-only genes (especially BIK and BMF). Up-regulation of BIK is associated with increased accessibility in an intronic region. SAHA, but not NKL54, also causes downregulation of BCL2L1 and decreases chromatin accessibility in three distinct regions of the BCL2L1 locus. Both inhibitors upregulate the expression of innate immunity genes and members of the MHC family. In conclusion, our studies explain the mechanisms of action of SAHA and cast doubt on the use of NKL54 as a single agent for efficient apoptosis induction.