NONO interacts with nuclear PKM2 and directs histone H3 phosphorylation to promote triple-negative breast cancer metastasis

Li, Q; Ci, H; Zhao, P; Yang, D; Zou, Y; Chen, P; Wu, D; Shangguan, W; Li, W; Meng, X; Xing, M; Chen, Y; Zhang, M; Chen, B; Kong, L; Zen, K; Huang, DCS; Jiang, ZW; Zhao, Q

Author(s): Li, Q; Ci, H; Zhao, P; Yang, D; Zou, Y; Chen, P; Wu, D; Shangguan, W; Li, W; Meng, X; Xing, M; Chen, Y; Zhang, M; Chen, B; Kong, L; Zen, K; Huang, DCS; Jiang, ZW; Zhao, Q;
Details: Publication Year 2025-03-10,Volume 44,Issue #1,Page 90
Journal Title: Journal of Experimental & Clinical Cancer Research
Abstract: BACKGROUND: Emerging evidence has revealed that PKM2 has oncogenic functions independent of its canonical pyruvate kinase activity, serving as a protein kinase that regulates gene expression. However, the mechanism by which PKM2, as a histone kinase, regulates the transcription of genes involved in triple-negative breast cancer (TNBC) metastasis remains poorly understood. METHODS: We integrated cellular analysis, including cell viability, proliferation, colony formation, and migration assays; biochemical assays, including protein interaction studies and ChIP; clinical sample analysis; RNA-Seq and CUT&Tag data; and xenograft or mammary-specific gene knockout mouse models, to investigate the epigenetic modulation of TNBC metastasis via NONO-dependent interactions with nuclear PKM2. RESULTS: We report that the transcription factor NONO directly interacts with nuclear PKM2 and directs PKM2-mediated phosphorylation of histone H3 at threonine 11 (H3T11ph) to promote TNBC metastasis. We show that H3T11ph cooperates with TIP60-mediated acetylation of histone H3 at lysine 27 (H3K27ac) to activate SERPINE1 expression and to increase the proliferative, migratory, and invasive abilities of TNBC cells in a NONO-dependent manner. Conditional mammary loss of NONO or PKM2 markedly suppressed SERPINE1 expression and attenuated the malignant progression of spontaneous mammary tumors in mice. Importantly, elevated expression of NONO or PKM2 in TNBC patients is positively correlated with SERPINE1 expression, enhanced invasiveness, and poor clinical outcomes. CONCLUSION: These findings revealed that the NONO-dependent interaction with nuclear PKM2 is key for the epigenetic modulation of TNBC metastasis, suggesting a novel intervention strategy for treating TNBC.
Publisher: BMC
Keywords: *Triple Negative Breast Neoplasms/metabolism/pathology/genetics; Humans; Mice; *Histones/metabolism; Animals; Female; *Thyroid Hormone-Binding Proteins; *Thyroid Hormones/metabolism; *Carrier Proteins/metabolism/genetics; Phosphorylation; *Membrane Proteins/metabolism/genetics; *Neoplasm Metastasis; Cell Line, Tumor; DNA-Binding Proteins/metabolism/genetics; Cell Proliferation; Chromobox Protein Homolog 5; Epigenomics; H3T11ph; Metastasis; Nono; Pkm2; Transcription; Triple-negative breast cancer
Research Division(s): Blood Cells And Blood Cancer
PubMed ID: 40059196
Publisher's Version: https://doi.org/10.1186/s13046-025-03343-5
Open Access at Publisher's Site: https://doi.org/10.1186/s13046-025-03343-5.
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-04-10 09:58:37

Last Modified: 2025-05-29 02:41:23