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. Swearingen, Lisa A. Carey, Jimena Giudice, Daniel Dominguez (), Christopher L. Holley () and Chad V. Pecot ()
Additional contact information
Yvonne L. Chao: University of North Carolina Lineberger Comprehensive Cancer Center
Katherine I. Zhou: University of North Carolina Lineberger Comprehensive Cancer Center
Kwame K. Forbes: University of North Carolina at Chapel Hill
Alessandro Porrello: University of North Carolina Lineberger Comprehensive Cancer Center
Gabrielle M. Gentile: University of North Carolina at Chapel Hill
Yinzhou Zhu: Duke University Medical Center
Aaron C. Chack: University of North Carolina Lineberger Comprehensive Cancer Center
Dixcy J. S. John Mary: University of Pittsburgh
Haizhou Liu: University of Pittsburgh
Eric Cockman: Duke University Medical Center
Lincy Edatt: University of North Carolina Lineberger Comprehensive Cancer Center
Grant A. Goda: University of North Carolina at Chapel Hill
Justin J. Zhao: Duke University Medical Center
Hala Abou Assi: Duke University Medical Center
Hannah J. Wiedner: University of North Carolina at Chapel Hill
Yihsuan Tsai: University of North Carolina Lineberger Comprehensive Cancer Center
Lily Wilkinson: University of North Carolina Lineberger Comprehensive Cancer Center
Amanda E. D. Swearingen: University of North Carolina Lineberger Comprehensive Cancer Center
Lisa A. Carey: University of North Carolina Lineberger Comprehensive Cancer Center
Jimena Giudice: University of North Carolina at Chapel Hill
Daniel Dominguez: University of North Carolina Lineberger Comprehensive Cancer Center
Christopher L. Holley: Duke University Medical Center
Chad V. Pecot: University of North Carolina Lineberger Comprehensive Cancer Center

Nature Communications, 2025, vol. 16, issue 1, 1-23

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-59406-w

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