Global landscape of 2-hydroxyisobutyrylation in human pancreatic cancer

Abstract

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.

A glimpse into novel acylations and their emerging role in regulating cancer metastasis

“…Additionally, Kcr and Khib modifications were also verified to contribute to gastrointestinal cancer metastasis, with elevated ENO1 Kcr in human CRC tissues promoting CRC cell invasion, migration, and growth by increasing ENO1 activity and upregulating tumor-associated expression [ 152 ]. Inhibiting Khib using MG149, a selective Tip60 inhibitor, significantly reduced the invasion, migration, and proliferation of PC cells [ 153 ].…”

Protein posttranslational modifications in health and diseases: Functions, regulatory mechanisms, and therapeutic implications

“… 565 Khib is widely distributed in PC, and treatment with the TIP60 inhibitor MG149 can significantly reduce the total Khib level in PC, which leads to the inhibition of PC cell proliferation, migration, and invasion. 498 Kcr is also involved in cancer regulation, with decreased levels observed in liver, gastric, and kidney cancers and increased levels in thyroid, esophageal, and PC. 566 In addition, p300‐mediated crotonylation enhances the expression of HNRNPA1, promoting HeLa cell malignancies.…”

“…Lower levels of the mitochondrial protein GCDH result in Kglu of the TF NRF2, leading to cell death, indicating that GCDH pathway inhibition is a potential therapeutic strategy for melanoma treatment 565 . Khib is widely distributed in PC, and treatment with the TIP60 inhibitor MG149 can significantly reduce the total Khib level in PC, which leads to the inhibition of PC cell proliferation, migration, and invasion 498 . Kcr is also involved in cancer regulation, with decreased levels observed in liver, gastric, and kidney cancers and increased levels in thyroid, esophageal, and PC 566 .…”

Biological functions and therapeutic potential of acylation by histone acetyltransferases

“…Pancreatic cancer Suppression of Khib levels inhibits proliferation, migration, and invasion of PC cells [47] Khib (↑)…”

“…MG149, a highly selective inhibitor of TIP60, markedly decreases total Khib levels in PC, and strongly inhibits PC cell proliferation and invasion [47]. Moon et al have shown that MG149 enhances the efficacy of sorafenib in advanced HCC, probably through upregulating cytotoxic endoplasmic reticulum stress [138].…”