Chemotherapy-induced S100A10 recruits KDM6A to facilitate OCT4-mediated breast cancer stemness
Open Access
- 1 September 2020
- journal article
- research article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 130 (9), 4607-4623
- https://doi.org/10.1172/jci138577
Abstract
Breast cancer stem cells (BCSCs) play a critical role in cancer recurrence and metastasis. Chemotherapy induces BCSC specification through increased expression of pluripotency factors, but how their expression is regulated is not fully understood. Here, we delineate a hypoxia-inducible factor 1 (HIF-1)-controlled pathway that epigenetically activates pluripotency factor gene transcription in response to chemotherapy. Paclitaxel induces HIF-1-dependent expression of S100A10, which forms a complex with ANXA2 that interacts with histone chaperone SPT6 and histone demethylase KDM6A. S100A10, ANXA2, SPT6, and KDM6A are recruited to OCT4 binding sites and KDM6A erases H3K27me3 chromatin marks, facilitating transcription of genes encoding the pluripotency factors NANOG, SOX2, and KLF4, which along with OCT4 are responsible for BCSC specification. Silencing of S100A10, ANXA2, SPT6, or KDM6A expression blocks chemotherapy-induced enrichment of BCSCs, impairs tumor initiation, and increases time to tumor recurrence after chemotherapy is discontinued. Pharmacological inhibition of KDM6A also impairs chemotherapy-induced BCSC enrichment. These results suggest that targeting HIF-1/S100A10-dependent and KDM6A-mediated epigenetic activation of pluripotency factor gene expression in combination with chemotherapy may block BCSC enrichment and improve clinical outcome.Keywords
Funding Information
- American Cancer Society (RP-16-239-06-COUN)
- Armstrong Family Foundation (N/A)
- Cindy Rosencrans Foundation (N/A)
- American Cancer Society (RP-16-239-06-COUN)
This publication has 79 references indexed in Scilit:
- Comprehensive molecular portraits of human breast tumoursNature, 2012
- Regulation of chromatin by histone modificationsCell Research, 2011
- EZH2 Promotes Expansion of Breast Tumor Initiating Cells through Activation of RAF1-β-Catenin SignalingCancer Cell, 2011
- Kruppel-like factor 4 (KLF4) is required for maintenance of breast cancer stem cells and for cell migration and invasionOncogene, 2011
- Biological and Molecular Heterogeneity of Breast Cancers Correlates with Their Cancer Stem Cell ContentCell, 2010
- An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1,809 patientsBreast Cancer Research and Treatment, 2009
- An embryonic stem cell–like gene expression signature in poorly differentiated aggressive human tumorsNature Genetics, 2008
- ALDH1 Is a Marker of Normal and Malignant Human Mammary Stem Cells and a Predictor of Poor Clinical OutcomeCell Stem Cell, 2007
- Genome Regulation by Polycomb and Trithorax ProteinsCell, 2007
- Core Transcriptional Regulatory Circuitry in Human Embryonic Stem CellsCell, 2005