Snord67 promotes breast cancer metastasis by guiding U6 modification and modulating the splicing landscape

Yvonne L Chao; Katherine I Zhou; Kwame K Forbes; Alessandro Porrello; Gabrielle M Gentile; Yinzhou Zhu; Aaron C Chack; Dixcy J S John Mary; Haizhou Liu; Eric Cockman; Lincy Edatt; Grant A Goda; Justin J Zhao; Hala Abou Assi; Hannah J Wiedner; Yihsuan Tsai; Lily Wilkinson; Amanda E D Van Swearingen; Lisa A Carey; Jimena Giudice; Daniel Dominguez; Christopher L Holley; Chad V Pecot

doi:10.1038/s41467-025-59406-w

Snord67 promotes breast cancer metastasis by guiding U6 modification and modulating the splicing landscape

Nat Commun. 2025 May 2;16(1):4118. doi: 10.1038/s41467-025-59406-w.

Authors

Yvonne L Chao^#^{1

2

3

4

5}, Katherine I Zhou^#^{1

6

7}, Kwame K Forbes^{7

8}, Alessandro Porrello^{1

7}, Gabrielle M Gentile^{9

10}, Yinzhou Zhu¹¹, Aaron C Chack^{1

7

10}, Dixcy J S John Mary³, Haizhou Liu³, Eric Cockman¹¹, Lincy Edatt^{1

7}, Grant A Goda^{7

12

13}, Justin J Zhao¹¹, Hala Abou Assi¹¹, Hannah J Wiedner^{9

10}, Yihsuan Tsai¹, Lily Wilkinson¹, Amanda E D Van Swearingen¹, Lisa A Carey^{1

2}, Jimena Giudice^{7

9

10

14}, Daniel Dominguez^{15

16

17

18

19}, Christopher L Holley²⁰, Chad V Pecot^{21

22

23}

Affiliations

¹ University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA.
² Division of Hematology & Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
³ Division of Hematology & Oncology, University of Pittsburgh, Pittsburgh, PA, USA.
⁴ University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA.
⁵ VA Pittsburgh Health System, Pittsburgh, PA, USA.
⁶ Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, NC, USA.
⁷ UNC RNA Discovery Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁸ Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁹ Department of Cell Biology & Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁰ Curriculum in Genetics and Molecular Biology (GMB), University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹¹ Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC, USA.
¹² Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹³ Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁴ McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁵ University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA. didoming@email.unc.edu.
¹⁶ UNC RNA Discovery Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. didoming@email.unc.edu.
¹⁷ Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. didoming@email.unc.edu.
¹⁸ Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. didoming@email.unc.edu.
¹⁹ Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. didoming@email.unc.edu.
²⁰ Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC, USA. cholley@duke.edu.
²¹ University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA. pecot@email.unc.edu.
²² Division of Hematology & Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. pecot@email.unc.edu.
²³ UNC RNA Discovery Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. pecot@email.unc.edu.

^# Contributed equally.

Abstract

Previously considered "housekeeping" genes, small nucleolar RNAs (snoRNAs) are increasingly understood to have wide-ranging functions in cancer, yet their role in metastasis has been less well studied. Here, we identify the snoRNA Snord67 as a regulator of lymph node (LN) metastasis in breast cancer. Snord67 expression is enriched in LN metastases in an immune-competent mouse model of female breast cancer. In an orthotopic breast cancer model, loss of Snord67 decreases LN metastasis. In a model of lymphatic metastasis, Snord67 loss decreases LN tumor growth and distant metastases. In breast cancer cell lines, Snord67 knockout results in loss of targeted 2'-O-methylation on U6 small nuclear RNA, as well as widespread changes in splicing. Together, these results demonstrate that Snord67 regulates splicing and promotes the growth of LN metastases and subsequent spread to distant metastases. SnoRNA-guided modifications of the spliceosome and regulation of splicing may represent a potentially targetable pathway in cancer.

MeSH terms

Animals
Breast Neoplasms* / genetics
Breast Neoplasms* / metabolism
Breast Neoplasms* / pathology
Cell Line, Tumor
Female
Gene Expression Regulation, Neoplastic
Humans
Lymphatic Metastasis / genetics
Mice
Neoplasm Metastasis
RNA Splicing* / genetics
RNA, Small Nuclear* / genetics
RNA, Small Nuclear* / metabolism
RNA, Small Nucleolar* / genetics
RNA, Small Nucleolar* / metabolism
Spliceosomes / metabolism

Substances

RNA, Small Nucleolar
U6 small nuclear RNA
RNA, Small Nuclear

Abstract

MeSH terms

Substances

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