Large-Scale Identification of Lysine Crotonylation Reveals Its Potential Role in Oral Squamous Cell Carcinoma.
Large-Scale Identification of Lysine Crotonylation Reveals Its Potential Role in Oral Squamous Cell Carcinoma.
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DOI：
10.2147/cmar.s424422
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发表时间：
2023
影响因子：
3.3
通讯作者：
中科院分区：
文献类型：
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作者：
赖氨酸巴豆化是一种新兴的翻译后修饰，参与了多种生物过程的调节。然而，它在口腔鳞状细胞癌(OSCC)中的作用仍不清楚。本研究旨在揭示口腔鳞状细胞癌在低氧条件下的全局性巴豆化，并探讨口腔鳞癌中巴豆化的潜在调控机制。采用高效液相色谱分离、亲和层析和高分辨质谱仪检测低氧条件下培养的CAL27细胞的差异巴豆化。获得的数据被进一步进行生物信息学分析，以揭示调控异常的巴豆化蛋白的相关生物学过程和途径。利用定点突变的质粒研究了巴豆化对热休克蛋白90α家族B类成员1(HAP90AB1)功能的影响。大规模的巴豆素组分析显示，在低氧条件下，CAL27细胞中的605个蛋白上有1563个巴豆化修饰位点。生物信息学分析显示，组蛋白巴豆化水平显著降低，而上调的巴豆化蛋白主要集中在非组蛋白蛋白中。值得注意的是，糖酵解相关蛋白在已鉴定的巴豆化蛋白中表现出显著的上调，其中HSP90AB1表现出最显著的变化。随后的实验结果证实，将HSP90AB1的赖氨酸265突变为沉默的精氨酸，会削弱其促进糖酵解的功能。我们的研究为口腔鳞状细胞癌中蛋白质在低氧条件下的巴豆化修饰提供了洞察力，并阐明了相关的生物学过程和途径。HSP90AB1在低氧条件下的巴豆化可增强口腔鳞癌的糖酵解调节能力，为研究低氧性口腔鳞癌中巴豆化的调控机制和口腔鳞癌治疗的潜在靶点提供了新的视角。
Lysine crotonylation, an emerging posttranslational modification, has been implicated in the regulation of diverse biological processes. However, its involvement in oral squamous cell carcinoma (OSCC) remains elusive. This study aims to reveal the global crotonylome in OSCC under hypoxic conditions and explore the potential regulatory mechanism of crotonylation in OSCC. Liquid-chromatography fractionation, affinity enrichment of crotonylated peptides, and high-resolution mass spectrometry were employed to detect differential crotonylation in CAL27 cells cultured under hypoxia. The obtained data were further subjected to bioinformatics analysis to uncover the involved biological processes and pathways of the dysregulated crotonylated proteins. A site-mutated plasmid was utilized to investigate the effect of crotonylation on Heat Shock Protein 90 Alpha Family Class B Member 1 (HAP90AB1) function. A large-scale crotonylome analysis revealed 1563 crotonylated modification sites on 605 proteins in CAL27 cells under hypoxia. Bioinformatics analysis revealed a significant decrease in histone crotonylation levels, while up-regulated crotonylated proteins were mainly concentrated in non-histone proteins. Notably, glycolysis-related proteins exhibited prominent up-regulation among the identified crotonylated proteins, with HSP90AB1 displaying the most significant changes. Subsequent experimental findings confirmed that mutating lysine 265 of HSP90AB1 into a silent arginine impaired its function in promoting glycolysis. Our study provides insights into the crotonylation modification of proteins in OSCC under hypoxic conditions and elucidates the associated biological processes and pathways. Crotonylation of HSP90AB1 in hypoxic conditions may enhance the glycolysis regulation ability in OSCC, offering novel perspectives on the regulatory mechanism of crotonylation in hypoxic OSCC and potential therapeutic targets for OSCC treatment.
影响因子：
4.8
作者：
Grubisha MJ;Sweet RA;MacDonald ML
通讯作者：
MacDonald ML