HDAC7‐mediated control of tumour microenvironment maintains proliferative and stemness competence of human mammary epithelial cells. Issue 8 (27th June 2019)

• Record Type: Journal Article
• Authors: Cutano, Valentina; Di Giorgio, Eros; Minisini, Martina; Picco, Raffaella; Dalla, Emiliano; Brancolini, Claudio
• Is Part Of: Molecular oncology. Volume 13:Issue 8(2019)
• Page Start: 1651
• Page End: 1668
• Publication Date: 2019-06-27
• Subjects: breast cancer -- CRISPR/Cas9 -- HDAC7 -- IL24 -- MEF2 -- RAS; Cancer -- Molecular aspects -- Periodicals; 616.994005
• DOI: 10.1002/1878-0261.12503
• Languages: English
• ISSNs: 1574-7891

Abstract

Abstract : HDAC7 is a pleiotropic transcriptional coregulator that controls different cellular fates. Here, we demonstrate that in human mammary epithelial cells, HDAC7 sustains cell proliferation and favours a population of stem‐like cells, by maintaining a proficient microenvironment. In particular, HDAC7 represses a repertoire of cytokines and other environmental factors, including elements of the insulin‐like growth factor signalling pathway, IGFBP6 and IGFBP7. This HDAC7‐regulated secretome signature predicts negative prognosis for luminal A breast cancers. ChIP‐seq experiments revealed that HDAC7 binds locally to the genome, more frequently distal from the transcription start site. HDAC7 can colocalize with H3K27‐acetylated domains and its deletion further increases H3K27ac at transcriptionally active regions. HDAC7 levels are increased in RAS‐transformed cells, in which this protein was required not only for proliferation and cancer stem‐like cell growth, but also for invasive features. We show that an important direct target of HDAC7 is IL24, which is sufficient to suppress the growth of cancer stem‐like cells. Abstract : Breast stem cells play key roles in tissue homeostasis and cancer development. We have discovered that the epigenetic regulator HDAC7, through the regulation of the microenvironment, influences the growth of breast stem cells. IL24 is a microenvironmental factor repressed by HDAC7 capable of inhibiting breast cancer stem cell growth. Overall, this study validates a new therapeutic axis for breast cancer treatment.