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.
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.
Bourguignon
Lilly Y W
LYW
Department of Medicine, Endocrine Unit (111N2), University of California at San Francisco and Veterans Affairs Medical Center, San Francisco, California 94121. Electronic address: lilly.bourguignon@ucsf.edu.
Xia
Weiliang
W
Department of Medicine, Endocrine Unit (111N2), University of California at San Francisco and Veterans Affairs Medical Center, San Francisco, California 94121.
Wong
Gabriel
G
Department of Medicine, Endocrine Unit (111N2), University of California at San Francisco and Veterans Affairs Medical Center, San Francisco, California 94121.
D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D019450:Genes, MDR; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism*; D011485:Protein Binding; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1; D037761:Sirtuins / Q000378:metabolism*; D051020:bcl-X Protein / Q000235:genetics*; D051176:beta Catenin / Q000378:metabolism*; D050880:p300-CBP Transcription Factors / Q000378:metabolism*
D018960:Hyaluronan Receptors; D016328:NF-kappa B; D051020:bcl-X Protein; D051176:beta Catenin; D006820:Hyaluronic Acid; D050880:p300-CBP Transcription Factors; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D037761:Sirtuins