SAHA Regulates Histone Acetylation, Butyrylation, and Protein Expression in Neuroblastoma

Emerging
evidence suggests that suberoylanilide hydroxamic acid
(SAHA), a clinically approved HDAC inhibitor for cutaneous T-cell
lymphoma, shows promising clinical benefits in neuroblastoma, the
most common extra cranial solid neoplasm with limited choice of therapeutic
intervention. However, the molecular mechanism under which the compound
exerts its antitumor effect remains elusive. Here we report a quantitative
proteomics study that determines changes of protein expression, histone
lysine acetylation, and butyrylation in response to SAHA treatment.
We detected and quantified 28 histone lysine acetylation and 18 histone
lysine butyrylation marks, most of which are dramatically induced
by SAHA. Importantly, we identified 11 histone Kbu sites
as novel histone marks in human cells. Furthermore, quantitative proteomic
analysis identified 5426 proteins, among which 510 proteins were up-regulated
and 508 proteins were down-regulated (significant p value <0.05). The subsequent bioinformatics analysis identified
distinct SAHA-response gene ontology (GO) categories and signaling
pathways, including cellular metabolism and DNA-dependent pathways.
Our study therefore reveals new histone epigenetic marks and offers
key insights into the molecular mechanism by which SAHA regulates
proteomic changes in neuroblastoma cells and identifies biomarker
candidates for SAHA.