Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, People's Republic of China.
Department of Radiotherapy, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China.
Clin Epigenetics. 2022 May 23;14(1):70. doi: 10.1186/s13148-022-01290-y.
Alterations in histone modifications have been reported to be related to tumorigenicity and tumor progression. However, whether histone modification can aid the classification of patients or influence clinical behavior in patients with colon cancer remains unclear. Therefore, this study aimed to evaluate histone modifier expression patterns using the unsupervised clustering of the transcriptomic expressions of 88 histone acetylation and methylation regulators.
In this study, by consensus clustering analysis based on the transcriptome data of 88 histone modification regulators, we identified four distinct expression patterns of histone modifiers associated with different prognoses, intrinsic fluorouracil sensitivities, biological pathways, and tumor microenvironment characteristics among 1372 colon cancer samples. In these four clusters, the HMC4 cluster represented a stroma activation phenotype characterized by both the worst prognosis and lowest response rates to fluorouracil treatment. Then, we established a scoring scheme comprising 155 genes designated as "HM_score" by using the Boruta algorithm to distinguish colon cancer patients within the HMC4 cluster. Patients with a high HM_score were considered to have high stromal pathway activation, high stromal fraction, and an unfavorable prognosis. Further analyses indicated that a high HM_score also correlated with reduced therapeutic benefits from fluorouracil chemotherapy. Moreover, through CRISPR library screening, ZEB2 was found to be a critical driver gene that mediates fluorouracil resistance, which is associated with histone modifier expression patterns.
This study highlights that characterizing histone modifier expression patterns may help better understand the epigenetic mechanisms underlying tumor heterogeneity in patients with colon cancer and provide more personalized therapeutic strategies.
组蛋白修饰的改变与肿瘤发生和肿瘤进展有关。然而，组蛋白修饰是否可以辅助患者分类或影响结肠癌患者的临床行为尚不清楚。因此，本研究旨在通过对 88 个组蛋白乙酰化和甲基化调节剂的转录组表达进行无监督聚类，评估组蛋白修饰剂的表达模式。
在本研究中，通过基于 88 个组蛋白修饰调节剂转录组数据的共识聚类分析，我们在 1372 个结肠癌样本中发现了与不同预后、内在氟尿嘧啶敏感性、生物学途径和肿瘤微环境特征相关的四种不同组蛋白修饰表达模式。在这四个聚类中，HMC4 聚类代表了一种基质激活表型，其特征是预后最差和对氟尿嘧啶治疗的反应率最低。然后，我们使用 Boruta 算法建立了一个包含 155 个基因的评分方案，命名为“HM_score”，以区分 HMC4 聚类中的结肠癌患者。HM_score 较高的患者被认为具有高基质途径激活、高基质分数和不良预后。进一步的分析表明，HM_score 较高还与氟尿嘧啶化疗获益减少相关。此外，通过 CRISPR 文库筛选，发现 ZEB2 是一种关键的驱动基因，它介导了与组蛋白修饰模式相关的氟尿嘧啶耐药性。
本研究强调，描述组蛋白修饰表达模式可以帮助更好地理解结肠癌患者肿瘤异质性的表观遗传机制，并提供更个性化的治疗策略。
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