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; Xiangqian Kong

doi:10.1038/s41467-024-55481-7

Defining ortholog-specific UHRF1 inhibition by STELLA for cancer therapy

Nat Commun. 2025 Jan 8;16(1):474. doi: 10.1038/s41467-024-55481-7.

Authors

Wenjing Bai^#^{1

2

3}, Jinxin Xu^#^{2

3}, Wenbin Gu^#^{1

2

3}, Danyang Wang^#³, Ying Cui^#⁴, Weidong Rong^{1

2

3}, Xiaoan Du^{2

3

5}, Xiaoxia Li^{3

5}, Cuicui Xia^{1

2

3}, Qingqing Gan^{2

3}, Guantao He^{3

5}, Huahui Guo^{1

2

3

5}, Jinfeng Deng³, Yuqiong Wu³, Ray-Whay Chiu Yen⁴, Srinivasan Yegnasubramanian⁴, Scott B Rothbart⁶, Cheng Luo^{7

8}, Linping Wu³, Jinsong Liu^{9

10}, Stephen B Baylin^{11

12}, Xiangqian Kong^{13

14

15

16}

Affiliations

¹ 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.
² State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China.
³ Institute of Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China.
⁴ The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
⁵ University of Chinese Academy of Sciences, Beijing, 100049, China.
⁶ Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, 49503, USA.
⁷ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
⁸ School of Pharmacy, Guizhou Medical University, Guiyang, 550004, China.
⁹ State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China. [email protected].
¹⁰ Institute of Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China. [email protected].
¹¹ The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA. [email protected].
¹² Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, 49503, USA. [email protected].
¹³ 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. [email protected].
¹⁴ State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China. [email protected].
¹⁵ Institute of Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China. [email protected].
¹⁶ The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA. [email protected].

^# Contributed equally.

PMID: 39774694
DOI: 10.1038/s41467-024-55481-7

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.

MeSH terms

Animals
CCAAT-Enhancer-Binding Proteins* / genetics
CCAAT-Enhancer-Binding Proteins* / metabolism
Cell Line, Tumor
DNA Methylation*
Humans
Mice
Neoplasms / drug therapy
Neoplasms / genetics
Neoplasms / metabolism
Protein Binding
Ubiquitin-Protein Ligases* / genetics
Ubiquitin-Protein Ligases* / metabolism

Substances

CCAAT-Enhancer-Binding Proteins
UHRF1 protein, human
Ubiquitin-Protein Ligases
Uhrf1 protein, mouse

Grants and funding

R01ES011858/U.S. Department of Health & Human Services | NIH | National Institute of Environmental Health Sciences (NIEHS)