Defining ortholog-specific UHRF1 inhibition by STELLA for cancer therapy

Wenjing Bai, Jinxin Xu, Wenbin Gu, Danyang Wang, Ying Cui, Weidong Rong, Xiaoan Du, Xiaoxia Li, Cuicui Xia, Qingqing Gan, Guantao He, Huahui Guo, Jinfeng Deng, Yuqiong Wu, Ray-Whay Chiu Yen, Srinivasan Yegnasubramanian, Scott B. Rothbart, Cheng Luo, Linping Wu, Jinsong Liu (), Stephen B. Baylin () and Xiangqian Kong ()
Additional contact information
Wenjing Bai: Chinese Academy of Sciences
Jinxin Xu: Chinese Academy of Sciences
Wenbin Gu: Chinese Academy of Sciences
Danyang Wang: Chinese Academy of Sciences
Ying Cui: The Johns Hopkins University School of Medicine
Weidong Rong: Chinese Academy of Sciences
Xiaoan Du: Chinese Academy of Sciences
Xiaoxia Li: Chinese Academy of Sciences
Cuicui Xia: Chinese Academy of Sciences
Qingqing Gan: Chinese Academy of Sciences
Guantao He: Chinese Academy of Sciences
Huahui Guo: Chinese Academy of Sciences
Jinfeng Deng: Chinese Academy of Sciences
Yuqiong Wu: Chinese Academy of Sciences
Ray-Whay Chiu Yen: The Johns Hopkins University School of Medicine
Srinivasan Yegnasubramanian: The Johns Hopkins University School of Medicine
Scott B. Rothbart: Van Andel Institute
Cheng Luo: Chinese Academy of Sciences
Linping Wu: Chinese Academy of Sciences
Jinsong Liu: Chinese Academy of Sciences
Stephen B. Baylin: The Johns Hopkins University School of Medicine
Xiangqian Kong: Chinese Academy of Sciences

Nature Communications, 2025, vol. 16, issue 1, 1-22

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-024-55481-7

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