Hyaluronan-mediated CD44 interaction with p300 and SIRT1 regulates beta-catenin signaling and NFkappaB-specific transcription activity leading to MDR1 and Bcl-xL gene expression and chemoresistance in breast tumor cells.

Abstract

In this study we have investigated hyaluronan (HA)-mediated CD44 (an HA receptor) interactions with p300 (a histone acetyltransferase) and SIRT1 (a histone deacetylase) in human breast tumor cells (MCF-7 cells). Specifically, our results indicate that HA binding to CD44 up-regulates p300 expression and its acetyltransferase activity that, in turn, promotes acetylation of beta-catenin and NFkappaB-p65 leading to activation of beta-catenin-associated T-cell factor/lymphocyte enhancer factor transcriptional co-activation and NFkappaB-specific transcriptional up-regulation, respectively. These changes then cause the expression of the MDR1 (P-glycoprotein/P-gp) gene and the anti-apoptotic gene Bcl-x(L) resulting in chemoresistance in MCF-7 cells. Our data also show that down-regulation of p300, beta-catenin, or NFkappaB-p65 in MCF-7 cells (by transfecting cells with p300-, beta-catenin-, or NFkappaB-p65-specific small interfering RNA) inhibits the HA/CD44-mediated beta-catenin/NFkappaB-p65 acetylation and abrogates the aforementioned transcriptional activities. Subsequently, there is a significant decrease in both MDR1 and Bcl-x(L) gene expression and an enhancement in caspase-3 activity and chemosensitivity in the breast tumor cells. Further analyses indicate that activation of SIRT1 (deacetylase) by resveratrol (a natural antioxidant) induces SIRT1-p300 association and acetyltransferase inactivation, leading to deacetylation of HA/CD44-induced beta-catenin and NFkappaB-p65, inhibition of beta-catenin-T-cell factor/lymphocyte enhancer factor and NFkappaB-specific transcriptional activation, and the impairment of MDR1 and Bcl-x(L) gene expression. All these multiple effects lead to an activation of caspase-3 and a reduction of chemoresistance. Together, these findings suggest that the interactions between HA/CD44-stimulated p300 (acetyltransferase) and resveratrol-activated SIRT1 (deacetylase) play pivotal roles in regulating the balance between cell survival versus apoptosis, and multidrug resistance versus sensitivity in breast tumor cells.

• Authors: Lilly Y W Bourguignon, Weiliang Xia, Gabriel Wong
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 284 Issue 5 Pg. 2657-2671 (Jan 30 2009) ISSN: 0021-9258 [Print] United States
• PMID: 19047049 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Hyaluronan Receptors
• NF-kappa B
• bcl-X Protein
• beta Catenin
• Hyaluronic Acid
• p300-CBP Transcription Factors
• SIRT1 protein, human
• Sirtuin 1
• Sirtuins

Topics

• Breast Neoplasms (genetics, metabolism, pathology)
• Cell Line, Tumor
• Drug Resistance, Neoplasm
• Gene Expression Regulation, Neoplastic (drug effects)
• Genes, MDR
• Humans
• Hyaluronan Receptors (metabolism)
• Hyaluronic Acid (pharmacology)
• NF-kappa B (metabolism)
• Protein Binding
• Signal Transduction (drug effects)
• Sirtuin 1
• Sirtuins (metabolism)
• bcl-X Protein (genetics)
• beta Catenin (metabolism)
• p300-CBP Transcription Factors (metabolism)