Abstract 1156: Shed syndecan-1 downregulates histone acetyltransferase activity and shuttles HGF to the nucleus of tumor and host cells

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA The cell surface heparan sulfate proteoglycan syndecan-1 (CD138) is expressed by myeloma tumor cells, is proteolytically shed from the cell surface and accumulates in the serum. High levels of serum syndecan-1 are an independent indicator of poor prognosis. Our lab has demonstrated that shed syndecan-1 drives myeloma tumor progression in vivo, but the mechanism(s) mediating this are not fully understood. The role of heparan sulfate proteoglycans on the cell surface and in the extracellular matrix has been extensively studied, but their presence and function within the nucleus is often overlooked. However, recent findings indicate that nuclear heparan sulfate has important regulatory functions. Based on preliminary findings, we hypothesized that shed syndecan-1 binds to the tumor cell surface and translocates to the nucleus where it regulates gene expression thereby promoting aggressive tumor behavior. We utilized murine myeloma cells which were grown in the presence of medium containing human shed syndecan-1. Strikingly, the shed syndecan-1 was rapidly taken up by these cells and translocated to the nucleus. Additionally, exogenous human shed syndecan-1 added to murine stromal cells also bound to the cell surface and translocated to the nucleus. This is the first demonstration that shed proteoglycans can translocate to the nucleus of cells. When stromal cells were grown in the presence of tumor-derived shed syndecan-1, acetylated histone H3 was decreased. Additionally, tumor cells engineered to express high levels of shed SDC1 have a 58% reduction in histone acetyltransferase activity. This may be due to syndecan-1 directly binding to p300/CBP-associated factor, a HAT enzyme. Moreover, HGF bound to shed syndecan-1 was shuttled to the nucleus of myeloma cells as a complex. Shed syndecan-1 and HGF translocation to the nucleus is dependent on intact heparan sulfate chains present on the syndecan-1 core protein. These data reveal a novel mechanism of tumor-host crosstalk whereby syndecan-1, shed by tumor cells, alters histone acetyltransferase activity and shuttles heparin-binding factors to the nucleus to reprogram cells and alter gene expression. Therapeutic regulation of syndecan-1 shedding, its binding to the cell surface or translocation to the nucleus represent novel strategies to control the progression of myeloma and other cancers. Citation Format: Mark Stewart, Vishnu Ramani, Ralph Sanderson. Shed syndecan-1 downregulates histone acetyltransferase activity and shuttles HGF to the nucleus of tumor and host cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1156. doi:10.1158/1538-7445.AM2014-1156