Bai Wenjing, Xu Jinxin, Gu Wenbin, Wang Danyang, Cui Ying, Rong Weidong, Du Xiaoan, Li Xiaoxia, Xia Cuicui, Gan Qingqing, He Guantao, Guo Huahui, Deng Jinfeng, Wu Yuqiong, Yen Ray-Whay Chiu, Yegnasubramanian Srinivasan, Rothbart Scott B, Luo Cheng, Wu Linping, Liu Jinsong, Baylin Stephen B, Kong Xiangqian
Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, CAS Key Laboratory of Regenerative Biology, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China.
State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China.
Nat Commun. 2025 Jan 8;16(1):474. doi: 10.1038/s41467-024-55481-7.
UHRF1 maintains DNA methylation by recruiting DNA methyltransferases to chromatin. In mouse, these dynamics are potently antagonized by a natural UHRF1 inhibitory protein STELLA, while the comparable effects of its human ortholog are insufficiently characterized, especially in cancer cells. Herein, we demonstrate that human STELLA (hSTELLA) is inadequate, while mouse STELLA (mSTELLA) is fully proficient in inhibiting the abnormal DNA methylation and oncogenic functions of UHRF1 in human cancer cells. Structural studies reveal a region of low sequence homology between these STELLA orthologs that allows mSTELLA but not hSTELLA to bind tightly and cooperatively to the essential histone-binding, linked tandem Tudor domain and plant homeodomain (TTD-PHD) of UHRF1, thus mediating ortholog-specific UHRF1 inhibition. For translating these findings to cancer therapy, we use a lipid nanoparticle (LNP)-mediated mRNA delivery approach in which the short mSTELLA, but not hSTELLA regions are required to reverse cancer-specific DNA hypermethylation and impair colorectal cancer tumorigenicity.
UHRF1通过将DNA甲基转移酶招募到染色质来维持DNA甲基化。在小鼠中，这些动态过程受到天然UHRF1抑制蛋白STELLA的强烈拮抗，而其人类同源物的类似作用尚未得到充分表征，尤其是在癌细胞中。在此，我们证明人类STELLA（hSTELLA）功能不足，而小鼠STELLA（mSTELLA）在抑制人类癌细胞中UHRF1的异常DNA甲基化和致癌功能方面完全有效。结构研究揭示了这些STELLA同源物之间低序列同源性的区域，该区域使得mSTELLA而非hSTELLA能够紧密且协同地结合到UHRF1的必需组蛋白结合、连接串联Tudor结构域和植物同源结构域（TTD-PHD），从而介导同源物特异性的UHRF1抑制。为了将这些发现转化为癌症治疗方法，我们采用脂质纳米颗粒（LNP）介导的mRNA递送方法，其中需要短的mSTELLA区域而非hSTELLA区域来逆转癌症特异性DNA高甲基化并损害结直肠癌的致瘤性。
