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BACKGROUND & AIMS: Epigenetic processes regulating gene expression contribute markedly to epithelial cell plasticity in colorectal carcinogenesis. The lysine methyltransferase SUV420H2 comprises an important regulator of epithelial plasticity and is primarily responsible for trimethylation of H4K20 (H4K20me3). Loss of H4K20me3 has been suggested as a hallmark of human cancer due to its interaction with DNMT1. However, the role of Suv4-20h2 in colorectal cancer is unknown.

METHODS

We examined the alterations in histone modifications in patient-derived colorectal cancer organoids. Patient-derived colorectal cancer organoids and mouse intestinal organoids were genetically manipulated for functional studies in patient-derived xenograft and orthotopic transplantation. Gene expression profiling, micrococcal nuclease assay, and chromatin immunoprecipitation were performed to understand epigenetic regulation of chromatin states and gene expression in patient-derived and mouse intestinal organoids.

RESULTS

We found that reduced H4K20me3 levels occurred predominantly in right-sided patient-derived colorectal cancer organoids, which were associated with increased chromatin accessibility. Re-compaction of chromatin by methylstat, a histone demethylase inhibitor, resulted in reduced growth selectively in subcutaneously grown tumors derived from right-sided cancers. Using mouse intestinal organoids, we confirmed that Suv4-20h2-mediated H4K20me3 is required for maintaining heterochromatin compaction and to prevent R-loop formation. Cross-species comparison of Suv4-20h2-depleted murine organoids with right-sided colorectal cancer organoids revealed a large overlap of gene signatures involved in chromatin silencing, DNA methylation, and stemness/Wnt signaling.

CONCLUSIONS

Loss of Suv4-20h2-mediated H4K20me3 drives right-sided colorectal tumorigenesis through an epigenetically controlled mechanism of chromatin compaction. Our findings unravel a conceptually novel approach for subtype-specific therapy of this aggressive form of colorectal cancer.

背景与目的

调节基因表达的表观遗传过程对结直肠肿瘤发生中的上皮细胞可塑性有重要贡献。赖氨酸甲基转移酶 SUV420H2 是上皮细胞可塑性的重要调节剂，主要负责 H4K20 的三甲基化（H4K20me3）。由于 H4K20me3 与 DNMT1 相互作用，其缺失被认为是人类癌症的一个标志。然而，Suv4-20h2 在结直肠癌中的作用尚不清楚。

方法

我们检查了患者来源的结直肠类器官中组蛋白修饰的改变。对患者来源的结直肠类器官和小鼠肠类器官进行基因操作，以进行患者来源的异种移植和原位移植中的功能研究。进行基因表达谱分析、微球菌核酸酶分析和染色质免疫沉淀，以了解患者来源和小鼠肠类器官中染色质状态和基因表达的表观遗传调控。

结果

我们发现，H4K20me3 水平降低主要发生在右侧患者来源的结直肠类器官中，这与染色质可及性增加有关。通过组蛋白去甲基酶抑制剂甲基stat 使染色质重新凝聚，导致源自右侧癌症的皮下生长肿瘤的生长选择性减少。使用小鼠肠类器官，我们证实 Suv4-20h2 介导的 H4K20me3 对于维持异染色质的紧缩和防止 R 环形成是必需的。在物种间比较 Suv4-20h2 缺失的鼠类类器官与右侧结直肠类器官时，发现在涉及染色质沉默、DNA 甲基化和干细胞/Wnt 信号的基因特征方面有很大的重叠。