A SPEN Complex Serves as a Scaffold to Coordinate Multiple Epigenetic Regulatory Mechanisms in Breast Cancer Stem Cells

There is substantial evidence that many cancers, including human breast cancer are hierarchically organized and driven by a cellular population that displays stem cell properties. These stem-like cells (CSC’s) mediate tumor metastasis and by virtue of their relative therapeutic resistance mediate tumor recurrence. Both normal and malignant stem cells are regulated through epigenetic mechanisms which involve DNA and histone modifications as well as noncoding RNAs. However, the mechanisms responsible for coordinating these multiple levels of epigenetic regulation in CSC’s remain elusive. Here, we identify a SPEN-Xist complex in breast CSC’s cells which, by virtue of inclusion of multiple epigenetic regulatory proteins, provides a scaffold for coordinating multiple levels of epigenetic regulation in these cells. Genetic knockdown of SPEN or XIST significantly reduces the CSC population as accessed by ALDH expression, sphere formation or tumor initiating capacity in xerograph models. Gene expression analysts suggests that the SPEN- XIST complex modulates multiple CSC regulatory pathways via the coordination of epigenetic modulatory proteins. This work has fundamental implications for understanding the epigenetic regulation of cancer stem cells as well as for developing strategies to target these cells