Snord67 promotes breast cancer metastasis by guiding U6 modification and modulating the splicing landscape
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.
Authors
- Eric Cockman
- Amanda E.D. Van Swearingen (ORCID: https://orcid.org/0000-0002-4287-9741)
- Jimena Giudice (ORCID: https://orcid.org/0000-0002-3330-7784)
- Hala Abou Assi (ORCID: https://orcid.org/0000-0003-1087-8805)
- Lincy Edatt (ORCID: https://orcid.org/0000-0001-7594-4012)
- Chad V. Pecot (ORCID: https://orcid.org/0000-0002-5250-2999)
- Lily Wilkinson
- Yinzhou Zhu (ORCID: https://orcid.org/0000-0003-0043-1321)
- Yvonne Chao
- Katherine I. Zhou (ORCID: https://orcid.org/0000-0001-6442-0475)
- Alessandro Porrello
- Gabrielle M. Gentile (ORCID: https://orcid.org/0000-0002-2669-1861)
- Christopher L. Holley (ORCID: https://orcid.org/0000-0002-2870-3352)
- Grant A. Goda (ORCID: https://orcid.org/0000-0002-7325-2490)
- Lisa A. Carey (ORCID: https://orcid.org/0000-0003-2388-4649)
- Dixcy Jaba Sheeba John Mary
- Daniel Dominguez (ORCID: https://orcid.org/0000-0002-8630-2776)
- Yi‐Hsuan Tsai (ORCID: https://orcid.org/0000-0003-2107-4300)
- Aaron C Chack (ORCID: https://orcid.org/0000-0003-3279-7192)
- Hannah J. Wiedner (ORCID: https://orcid.org/0000-0002-5919-5944)
- Haizhou Liu (ORCID: https://orcid.org/0000-0001-5111-5295)
- Jinqiu Zhao (ORCID: https://orcid.org/0000-0001-9745-3230)
- Kwame Forbes (ORCID: https://orcid.org/0000-0002-9781-7900)
Institutions
- University of North Carolina at Chapel Hill (US)
- University of North Carolina Health Care (US)
- University of Pittsburgh (US)
- Duke University (US)
- Duke Medical Center (US)
- UPMC Hillman Cancer Center (US)
- VA Pittsburgh Healthcare System (US)
- University of Pittsburgh Medical Center (US)
- UNC Lineberger Comprehensive Cancer Center
Publication Details
- Journal
- Nature Communications
- Published
- 2025-05-02
- DOI
- https://doi.org/10.1038/s41467-025-59406-w
- Citations
- 2
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- National Cancer Institute