Abstract #3569: Hyaluronan-mediated CD44 interaction with p300 and SIRT1 regulates \#946;-Catenin signaling and NF\#954;B -specific transcription activity leading to MDR1 and Bcl-x_L gene expression and chemoresistance in breast tumor cells

In this study we have investigated hyaluronan (HA)-mediated CD44 (a HA receptor) interactions with p300 (a histone acetyltransferase, HAT) and SIRT1 (a histone deacetylase, HDAC) in human breast tumor cells (MCF-7 cells). The focus of this study is to examine the roles that p300 and SIRT1 play in controlling \#946;-catenin and NF\#954;B signaling, as well as chemotherapeutic drug [e.g., doxorubicin and etoposide (VP-16)] responses, in MCF-7 cells. Specifically, our results indicate that HA binding to CD44 upregulates p300 expression and its acetyltransferase activity which, in turn, promotes acetylation of \#946;-catenin and NF\#954;B-p65 leading to activation of \#946;-catenin-associated T-cell factor/lymphocyte enhancer factor (TCF/LEF) transcriptional co-activation and NF\#954;B-specific transcriptional upregulation, 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 downregulation of p300, \#946;-catenin or NF\#954;B-p65 in MCF-7 cells [by transfecting cells with p300-, \#946;-catenin- or NF\#954;B-p65-specific small interfering RNA (siRNA)] inhibits the HA/CD44-mediated \#946;-catenin/NF\#954;B-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 \#946;-catenin and NF\#954;B-p65, inhibition of \#946;-catenin-TCF/LEF and NF\#954;B-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 vs. apoptosis, and multi-drug resistance vs. sensitivity in breast tumor cells.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3569.