Methylation of histone H3 lysine 36 is a barrier for therapeutic interventions of head and neck squamous cell carcinoma.-猫眼课题宝

DOI：

10.1101/2023.11.06.565847

发表时间：

2023-11

期刊：

bioRxiv

影响因子：

通讯作者：

中科院分区：

其他

文献类型：

作者：

Lucas D. Caeiro;Yuichiro Nakata;Rodrigo L. Borges;Liliana Garcia-Martinez;Carolina P. Bañuelos;S. Stransky;Ho Lam Chan;John P. Brabson;Diana Domínguez;Yusheng Zhang;Peter W. Lewis;Salvador Aznar-Benitah;Luisa Cimmino;Daniel Bilbao;Simone Sidoli;Ramiro E. Verdun;L. Morey

大约20%的头颈部鳞状细胞癌（HNSCC）由于组蛋白甲基化酶NSD 1突变或组蛋白H3（H3 K36 M）中的赖氨酸-甲硫氨酸突变而表现出组蛋白H3（H3 K36 me）赖氨酸36甲基化降低。H3 K36 me的这种改变是否可以用于治疗干预仍然是未知的。在这里，我们表明表达H3 K36 M的HNSCC模型可以分为两组：显示H3 K27 me 3异常积累的模型和保持H3 K27 me 3稳定水平的模型。第一组显示增殖减少、基因组不稳定性和对遗传毒性剂（如PARP 1/2抑制剂）的敏感性增加。相反，具有稳定H3 K27 me 3水平的H3 K36 M HNSCC模型不表现出这些特征，除非通过DNA低甲基化剂或通过抑制H3 K27 me 3去甲基化酶KDM 6 A/B升高H3 K27 me 3水平。从机制上讲，我们发现H3 K36 M通过直接阻碍组蛋白甲基转移酶NSD 3和组蛋白脱甲基酶LSD 2的活性来降低H3 K36 me。值得注意的是，我们发现由H3 K36 M表达诱导的异常H3 K27 me 3水平不是HNSCC中真正的表观遗传标记，因为它需要H3 K36 M的连续表达才能遗传。此外，H3 K36 M HNSCC模型对PARP 1/2抑制剂的敏感性增加仅取决于H3 K27 me 3水平的增加。事实上，异常高的H3 K27 me 3水平降低了BRCA 1和FANCD 2依赖的DNA修复，导致对DNA断裂和复制应激的更高敏感性。最后，为了支持我们的体外发现，单独的PARP 1/2抑制剂在具有升高的H3 K27 me 3的H3 K36 M HNSCC异种移植模型中降低肿瘤负荷，而在具有一致的H3 K27 me 3水平的H3 K36 M HNSCC异种移植模型中，PARP 1/2抑制剂和上调H3 K27 me 3的药剂的组合被证明是成功的。总之，我们的研究结果强调了H3 K36和H3 K27甲基化之间的微妙平衡，这对维持基因组稳定性至关重要。这种平衡为H3 K36 me缺陷型肿瘤患者提供了有希望的治疗机会。

Approximately 20% of head and neck squamous cell carcinomas (HNSCC) exhibit reduced methylation on lysine 36 of histone H3 (H3K36me) due to mutations in histone methylase NSD1 or a lysine-to-methionine mutation in histone H3 (H3K36M). Whether such alterations of H3K36me can be exploited for therapeutic interventions is still unknown. Here, we show that HNSCC models expressing H3K36M can be divided into two groups: those that display aberrant accumulation of H3K27me3 and those that maintain steady levels of H3K27me3. The first group shows decreased proliferation, genome instability, and increased sensitivity to genotoxic agents, such as PARP1/2 inhibitors. In contrast, the H3K36M HNSCC models with steady H3K27me3 levels do not exhibit these characteristics unless H3K27me3 levels are elevated, either by DNA hypomethylating agents or by inhibiting the H3K27me3 demethylases KDM6A/B. Mechanistically, we found that H3K36M reduces H3K36me by directly impeding the activities of the histone methyltransferase NSD3 and the histone demethylase LSD2. Notably, we found that aberrant H3K27me3 levels induced by H3K36M expression is not a bona fide epigenetic mark in HNSCC since it requires continuous expression of H3K36M to be inherited. Moreover, increased sensitivity of H3K36M HNSCC models to PARP1/2 inhibitors solely depends on the increased H3K27me3 levels. Indeed, aberrantly high H3K27me3 levels decrease BRCA1 and FANCD2-dependent DNA repair, resulting in higher sensitivity to DNA breaks and replication stress. Finally, in support of our in vitro findings, a PARP1/2 inhibitor alone reduce tumor burden in a H3K36M HNSCC xenograft model with elevated H3K27me3, whereas in a H3K36M HNSCC xenograft model with consistent H3K27me3 levels, a combination of PARP1/2 inhibitors and agents that upregulate H3K27me3 proves to be successful. In conclusion, our findings underscore a delicate balance between H3K36 and H3K27 methylation, essential for maintaining genome stability. This equilibrium presents promising therapeutic opportunities for patients with H3K36me-deficient tumors.

Methylation of histone H3 lysine 36 is a barrier for therapeutic interventions of head and neck squamous cell carcinoma.

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