生物
组蛋白H3
表观遗传学
组蛋白
组蛋白甲基化
甲基化
癌症研究
基因组不稳定性
甲基转移酶
组蛋白甲基转移酶
脱甲基酶
EZH2型
PARP1
DNA甲基化
PRC2
DNA损伤
遗传学
DNA
基因表达
聚ADP核糖聚合酶
基因
聚合酶
作者
Lucas Caeiro,Yoshihisa Nakata,Rodrigo L. Borges,M. Zha,Liliana Garcia-Martinez,Carolina P. Bañuelos,Stephanie Stransky,Tong Liu,Ho Lam Chan,J A Brabson,Diana Domínguez,Yusheng Zhang,Peter W. Lewis,Salvador Aznar Benitah,Luisa Cimmino,Daniel Bilbao,Simone Sidoli,Zheng Wang,Ramiro E. Verdún,Lluís Morey
标识
DOI:10.1101/gad.351408.123
摘要
Approximately 20% of head and neck squamous cell carcinomas (HNSCCs) 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 former group exhibits reduced proliferation, genome instability, and heightened sensitivity to genotoxic agents like PARP1/2 inhibitors. Conversely, H3K36M HNSCC models with constant H3K27me3 levels lack these characteristics unless H3K27me3 is elevated by DNA hypomethylating agents or inhibiting H3K27me3 demethylases KDM6A/B. Mechanistically, H3K36M reduces H3K36me by directly impeding the activities of the histone methyltransferase NSD3 and the histone demethylase LSD2. Notably, aberrant H3K27me3 levels induced by H3K36M expression are not a bona fide epigenetic mark because they require continuous expression of H3K36M to be inherited. Moreover, increased sensitivity to PARP1/2 inhibitors in H3K36M HNSCC models depends solely on elevated H3K27me3 levels and diminishing BRCA1- and FANCD2-dependent DNA repair. Finally, a PARP1/2 inhibitor alone reduces tumor burden in a H3K36M HNSCC xenograft model with elevated H3K27me3, whereas in a model with consistent H3K27me3, a combination of PARP1/2 inhibitors and agents that up-regulate H3K27me3 proves to be successful. These findings underscore the crucial balance between H3K36 and H3K27 methylation in maintaining genome instability, offering new therapeutic options for patients with H3K36me-deficient tumors.
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