Identification of a cancer stem cell-specific function for the histone deacetylases, HDAC1 and HDAC7, in breast and ovarian cancer

Abstract

Tumours are comprised of a highly heterogeneous population of cells, of which only a small subset of stem-like cells possess the ability to regenerate tumours in vivo. These cancer stem cells (CSCs) represent a significant clinical challenge as they are resistant to conventional cancer therapies and play essential roles in metastasis and tumour relapse. Despite this realization and great interest in CSCs, it has been difficult to develop CSC-targeted treatments due to our limited understanding of CSC biology. Here, we present evidence that specific histone deacetylases (HDACs) play essential roles in the CSC phenotype. Utilizing a novel CSC model, we discovered that the HDACs, HDAC1 and HDAC7, are specifically over-expressed in CSCs when compared to non-stem-tumour-cells (nsTCs). Furthermore, we determine that HDAC1 and HDAC7 are necessary to maintain CSCs, and that over-expression of HDAC7 is sufficient to augment the CSC phenotype. We also demonstrate that clinically available HDAC inhibitors (HDACi) targeting HDAC1 and HDAC7 can be used to preferentially target CSCs. These results provide actionable insights that can be rapidly translated into CSC-specific therapies.

HDAC7‐mediated control of tumour microenvironment maintains proliferative and stemness competence of human mammary epithelial cells

“…Up-regulation of HDAC7 expression in rodent and human cells can cooperate for the neoplastic transformation (Di Giorgio et al, 2013;Lei et al, 2017;Paluvai et al, 2018;Rad et al, 2010). In breast and ovary cancers, HDAC7 is highly expressed in cancer stem cells and it is involved in stem cell maintenance (Witt et al, 2017). Although there are evidences for a role of HDAC7 in the neoplastic transformation, the genetic and epigenetic changes under HDAC7 supervision are not fully elucidated.…”

Lung cancer stem cells—origin, characteristics and therapy

“…Thus, additional in vitro and in vivo assays that affirm the self-propagating and self-renewal property of CSCs might be necessary to certainly isolate the CSCs. However, CSCs exhibit phenotypic instability once they are outside the solid tissue which makes the precise identification hard to achieve (65).…”

HDAC2 and PCNA expression is correlated to decreasing of endoxifen sensitivity in human breast cancer stem cells ALDH+

“…Penelitian kami sebelumnya menggunakan jaringan kanker payudara mengungkapkan bahwa ekspresi gen histone deacetylase 2 (HDAC2) dan proliferating cell nuclear antigen (PCNA) ditemukan perbedaan signifikan setelah terapi neoajuvan hormon dan kemoterapi. Penelitian ini bertujuan untuk menganalisis hubungan antara ekspresi HDAC2 dan PCNA dengan kelangsungan hidup sel punca kanker payudara dengan penanda aldehyde dehydrogenase + (ALDH+) yang diberi perlakuan endoksifen.Metode: Sampel adalah BCSC primer manusia ALDH+ yang diberi perlakuan endoksifen 4 uM masingmasing selama 2,4,6,8,10,12,14 hari. Viabilitas sel dilihat dengan menggunakan trypan blue dan ekspresi mRNA HDAC2 dan PCNA ditentukan menggunakan qRT-PCR.Hasil: Viabilitas BCSCs ALDH + menurun setelah 2 sampai 4 hari pemberian endoksifen.…”