RNA-seq data from TAS4464, a NEDD8-activating enzyme inhibitor, activates both intrinsic and extrinsic apoptotic pathways via c-Myc-mediated regulation in acute myeloid leukemia

TAS4464, a potent, selective small molecule NEDD8-activating enzyme (NAE)
inhibitor, leads to inactivation of cullin-RING E3 ubiquitin ligases
(CRLs) and consequent accumulations of its substrate proteins. Here, we
investigated the antitumor properties and action mechanism of TAS4464 in
acute myeloid leukemia (AML). TAS4464 induced apoptotic cell death in
various AML cell lines. TAS4464 treatments resulted in the
activation of both the caspase-9-mediated in intrinsic apoptotic pathway
and caspase-8-mediated extrinsic apoptotic pathway in AML cells; combined
treatment with inhibitors of these caspases markedly diminished
TAS4464 induced apoptosis. In each apoptotic pathway, TAS4464
induced the mRNA transcription of the intrinsic proapoptotic factor NOXA
and decreased that of the extrinsic antiapoptotic factor c-FLIP.
RNA-sequencing analysis showed that the signaling pathway of the CRL
substrate c-Myc was enriched after TAS4464 treatment. Chromatin
immunoprecipitation (ChIP) assay revealed that TAS4464 induced
c-Myc bound to the PMAIP1 (encoding NOXA)
and CFLAR (encoding c-FLIP) promoter regions, and
siRNA-mediated c-Myc knockdown neutralized both TAS4464-mediated NOXA
induction and c-FLIP downregulation. TAS4464 activated both caspase-8 and
caspase-9 along with an increase in NOXA and a decrease in c-FLIP,
resulting in complete tumor remission in a human AML xenograft model.
These findings suggest that NAE inhibition leads to anti-AML activity via
a novel c-Myc-dependent apoptosis induction mechanism.