MECP2
化学
表观遗传学
甲基化
嵌合体(遗传学)
DNA甲基化
蛋白质水解
蛋白质降解
蛋白酶体
癌症研究
生物化学
DNA
生物
基因表达
基因
酶
表型
作者
Zhen Wang,Jing Liu,Xing Qiu,Dingpeng Zhang,Hiroyuki Inuzuka,Li Chen,He Chen,Ling Xie,H. Ümit Kanıskan,Xian Chen,Jian Jin,Wenyi Wei
摘要
Methyl-CpG-binding protein 2 (MeCP2), a reader of DNA methylation, has been extensively investigated for its function in neurological and neurodevelopmental disorders. Emerging evidence indicates that MeCP2 exerts an oncogenic function in cancer; however, the endeavor to develop a MeCP2-targeted therapy remains a challenge. This work attempts to address it by introducing a methylated nucleotide-based targeting chimera termed methyl-proteolysis-targeting chimera (methyl-PROTAC). The methyl-PROTAC incorporates a methylated cytosine into an oligodeoxynucleotide moiety to recruit MeCP2 for targeted degradation in a von Hippel-Lindau- and proteasome-dependent manner, thus displaying antiproliferative effects in cancer cells reliant on MeCP2 overexpression. This selective cytotoxicity endows methyl-PROTAC with the capacity to selectively eliminate cancer cells that are addicted to the overexpression of the MeCP2 oncoprotein. Furthermore, methyl-PROTAC-mediated MeCP2 degradation induces apoptosis in cancer cells. These findings underscore the therapeutic potential of methyl-PROTAC to degrade undruggable epigenetic regulatory proteins. In summary, the development of methyl-PROTAC introduces an innovative strategy by designing a modified nucleotide-based degradation approach for manipulating epigenetic factors, thereby representing a promising avenue for the advancement of PROTAC-based therapeutics.
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