Tu Zewei, Wu Lei, Luo Haitao, Li Jingying, Lv Shigang, Ye Minhua, Liu Feng, Tao Chuming, Zhu Xingen, Huang Kai
Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China.
East China Institute of Digital Medical Engineering, Shangrao, China.
Front Mol Biosci. 2021 Feb 26;8:587516. doi: 10.3389/fmolb.2021.587516. eCollection 2021.
Lysine acetylation modification, which has key roles in cellular homeostasis as well as cancer malignancy, is dynamically regulated by lysine acetylation regulators (LARs). In our study, we found that most of 33 evaluated LARs were differentially expressed among 1,125 gliomas grouped by different clinicopathological characteristics. Consensus clustering was applied to 33 LARs, resulting in three glioma subtypes (LA1, 2, and 3). The LA3 subgroup was associated with the poorest clinical outcome, higher WHO grade, fewer isocitrate dehydrogenase mutations, and lower frequency of 1p/19q codeletion. Furthermore, gene set enrichment analysis indicated that eight tumor hallmarks were highly enriched in the LA3 subgroup. These results suggested that LARs are significantly related to glioma malignancy. We then designed a LAR-signature based on 14 overall survival (overall survival)-related LARs, and showed that the LAR-signature possesses strong and independent prognostic value for glioma patients in both training and validation datasets. Moreover, by interrogating single nucleotide polymorphism and copy number variation (CNV) data in The Genome Atlas dataset, we found that higher score of our risk signature is correlated with the hypermutation status of gliomas and that HDAC1(1p) was one of the oncogenes lost in 1p/19q codeletion events, while SIRT2(19q) and EP300(22q) may act as tumor suppressors in gliomas with 19q or 22q deletions, respectively. In conclusion, LARs are critical for the malignant development of gliomas, and our results are useful for prognostic stratification and development of novel assessment strategies for the prognosis of glioma patients.
赖氨酸乙酰化修饰在细胞稳态以及癌症恶性肿瘤中起着关键作用，它受到赖氨酸乙酰化调节因子（LARs）的动态调控。在我们的研究中，我们发现，在按不同临床病理特征分组的1125例胶质瘤中，33个评估的LARs中的大多数存在差异表达。对33个LARs进行一致性聚类，产生了三种胶质瘤亚型（LA1、2和3）。LA3亚组与最差的临床结果、更高的世界卫生组织分级、更少的异柠檬酸脱氢酶突变以及更低的1p/19q共缺失频率相关。此外，基因集富集分析表明，八个肿瘤特征在LA3亚组中高度富集。这些结果表明，LARs与胶质瘤恶性程度显著相关。然后，我们基于14个与总生存期（总生存期）相关的LARs设计了一个LAR特征，并表明该LAR特征在训练和验证数据集中对胶质瘤患者具有强大且独立的预后价值。此外，通过查询基因组图谱数据集中的单核苷酸多态性和拷贝数变异（CNV）数据，我们发现我们的风险特征得分越高与胶质瘤的高突变状态相关，并且HDAC1(1p)是1p/19q共缺失事件中丢失的致癌基因之一，而SIRT2(19q)和EP300(22q)可能分别在具有19q或22q缺失的胶质瘤中作为肿瘤抑制因子发挥作用。总之，LARs对胶质瘤的恶性发展至关重要，我们的结果有助于胶质瘤患者预后分层和新的预后评估策略的开发。
