NOXA Accentuates Apoptosis Induction by a Novel Histone Deacetylase Inhibitor

Abstract

Epigenetic modifiers of the histone deacetylase (HDAC) family are often dysregulated in cancer cells. Experiments with small molecule HDAC inhibitors (HDACi) have proven that HDACs are a vulnerability of transformed cells. We evaluated a novel hydroxamic acid-based HDACi (KH16; termed yanostat) in human pancreatic ductal adenocarcinoma (PDAC) cells, short- and long-term cultured colorectal cancer (CRC) cells, and retinal pigment epithelial cells. We show that KH16 induces cell cycle arrest and apoptosis, both time and dose dependently in PDAC and CRC cells. This is associated with altered expression of BCL2 family members controlling intrinsic apoptosis. Recent data illustrate that PDAC cells frequently have an altered expression of the pro-apoptotic BH3-only protein NOXA and that HDACi induce an accumulation of NOXA. Using PDAC cells with a deletion of NOXA by CRISPR-Cas9, we found that a lack of NOXA delayed apoptosis induction by KH16. These results suggest that KH16 is a new chemotype of hydroxamic acid HDACi with superior activity against solid tumor-derived cells. Thus, KH16 is a scaffold for future research on compounds with nanomolar activity against HDACs.

Histone deacetylase inhibitors modulate hormesis in leukemic cells with mutant FMS-like tyrosine kinase-3

“…This includes the development of nanomolar HDACi with a low impact on normal cells and the identification of effective drug combinations [ 7 , 13 ]. KH16 and KH29 are recently developed HDACi, which we have named yanostat-1/yanostat-2 [ 12 , 14 ]. We reveal that their inhibitory profiles are superior to those of SAHA and MS-275 in AML cells carrying FLT3-ITD.…”

“…Human embryonic kidney and retinal pigment epithelial (RPE1) cells do not undergo apoptosis when they are exposed to KH16 and KH29 [ 12 , 14 ]. We extended these analyses.…”