HDAC6 Deacetylates HMGN2 to Regulate Stat5a Activity and Breast Cancer Growth.

Abstract

Stat5a is a transcription factor utilized by several cytokine/hormone receptor signaling pathways that promotes transcription of genes associated with proliferation, differentiation, and survival of cancer cells. However, there are currently no clinically approved therapies that directly target Stat5a, despite ample evidence that it contributes to breast cancer pathogenesis. Here, deacetylation of the Stat5a coactivator and chromatin-remodeling protein HMGN2 on lysine residue K2 by HDAC6 promotes Stat5a-mediated transcription and breast cancer growth. HDAC6 inhibition both in vitro and in vivo enhances HMGN2 acetylation with a concomitant reduction in Stat5a-mediated signaling, resulting in an inhibition of breast cancer growth. Furthermore, HMGN2 is highly acetylated at K2 in normal human breast tissue, but is deacetylated in primary breast tumors and lymph node metastases, suggesting that targeting HMGN2 deacetylation is a viable treatment for breast cancer. Together, these results reveal a novel mechanism by which HDAC6 activity promotes the transcription of Stat5a target genes and demonstrate utility of HDAC6 inhibition for breast cancer therapy.

IMPLICATIONS:

HMGN2 deacetylation enhances Stat5a transcriptional activity, thereby regulating prolactin-induced gene transcription and breast cancer growth. Mol Cancer Res; 14(10); 994-1008. ©2016 AACR.

• Authors: Terry R Medler, Justin M Craig, Alyson A Fiorillo, Yvonne B Feeney, J Chuck Harrell, Charles V Clevenger
• Journal: Molecular cancer research : MCR (Mol Cancer Res) Vol. 14 Issue 10 Pg. 994-1008 (10 2016) ISSN: 1557-3125 [Electronic] United States
• PMID: 27358110 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• HMGN2 Protein
• STAT5 Transcription Factor
• STAT5A protein, human
• Tumor Suppressor Proteins
• HDAC6 protein, human
• Histone Deacetylase 6
• Histone Deacetylases
• Lysine

Topics

• Acetylation
• Animals
• Breast Neoplasms (genetics, metabolism, pathology)
• Cell Line, Tumor
• Cell Proliferation
• Female
• Gene Expression Regulation, Neoplastic
• HMGN2 Protein (metabolism)
• Histone Deacetylase 6
• Histone Deacetylases (metabolism)
• Humans
• Lysine (metabolism)
• MCF-7 Cells
• Mice
• Neoplasm Metastasis
• Neoplasm Transplantation
• STAT5 Transcription Factor (genetics)
• Transcription, Genetic
• Tumor Suppressor Proteins (genetics)