A novel peptide 66CTG stabilizes Myc proto-oncogene protein to promote triple-negative breast cancer growth

A novel peptide 66CTG stabilizes Myc proto-oncogene protein to promote triple-negative breast cancer growth

Abstract Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer that lacks reliable targets for diagnosis and therapy. Non-coding RNA (ncRNA)-encoded products hold promise for addressing this unmet need. By analyzing the reported ribosomal RNA sequencing data, combined w...

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Main Authors: Huichun Liang, Fubing Li, Huan Fang, Wenlong Ren, Zhongmei Zhou, Jiecheng Wang, Jialing Liu, Yongjia Tang, Xue Liu, Yingying Wu, Jing Peng, Chuanyu Yang, Jiayi Chen, Yuting Fei, Yujie Shi, Dewei Jiang, Nu Zhang, Ceshi Chen
Format: Article
Language:English
Published: Nature Publishing Group 2025-07-01
Series:Signal Transduction and Targeted Therapy
Online Access:https://doi.org/10.1038/s41392-025-02298-5
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Summary:Abstract Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer that lacks reliable targets for diagnosis and therapy. Non-coding RNA (ncRNA)-encoded products hold promise for addressing this unmet need. By analyzing the reported ribosomal RNA sequencing data, combined with the TCGA, ORFfinder, SmProt databases, we identified CDKN2B-AS1, a TNBC-upregulated lncRNA encoding a 66-amino-acid peptide via CUG-initiated translation. CRISPR-Cas9 gene editing and mass spectrometry confirmed endogenous expression of this peptide, designated 66CTG, in TNBC cells. Functionally independently of its host RNA, 66CTG promoted the proliferation of TNBC cells and the tumor growth of TNBC xenograft by stabilizing c-Myc protein and enhancing Cyclin D1 transcription. Immunohistochemistry of 89 clinical TNBC paraffin samples revealed positive correlations among 66CTG, c-Myc, and Cyclin D1 expression levels. Mechanistically, co-immunoprecipitation and ubiquitination assays revealed that 66CTG stabilized c-Myc by competitively interacting with FBW7α, an E3 ligase responsible for recognizing 66CTG CPDS56/S60 motif which phosphorylated by GSK-3β during the late G1 phase. In conclusion, our findings suggest 66CTG has potential to be developed as a target for TNBC diagnosis and therapy. Furthermore, it unveils a regulatory axis wherein 66CTG stabilizes c-Myc by interacting with FBW7α, offering a new mechanistic explanation for c-Myc overexpression in TNBC. Patients co-overexpressing 66CTG, c-Myc, and Cyclin D1 may benefit from therapies targeting this axis.
ISSN:2059-3635

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