As a new type of post-translational modification (PTM),
lysine 2-hydroxyisobutyrylation (Khib) was firstly identified in
histones and functioned as a regulator of transactivation in mammals. However, the role of Khib
proteins remains to be investigated. Here, we firstly identified 10,367 Khib sites on 2,325 modified
proteins in seven patients with
pancreatic cancer by applying liquid chromatography with tandem mass spectrometry (LC-MS/MS) qualitative proteomics techniques. Among them, 27 Khib-modified sites were identified in
histones. Bioinformatics analysis revealed that the Khib-modified
proteins were mainly distributed in the cytoplasm and enhanced in metabolic pathways, including glycolysis/gluconeogenesis, the tricarboxylic acid cycle (TCA cycle), and
fatty acid degradation. In an overlapping comparison of
lysine 2-hydroxyisobutyrylation, succinylation, and acetylation in humans, 105
proteins with 80 sites were modified by all three PTMs, suggesting there may be a complex network among the different modified
proteins and sites. Furthermore,
MG149, which was identified as a Tip60 inhibitor, significantly decreased the total Khib modification level in
pancreatic cancer (PC) and strongly suppressed PC's proliferation, migration, and invasion ability. Overall, our study is the first profiling of
lysine 2-hydroxyisobutyrylome and provides a new database for better investigating Khib in PC.