The inhibition of KDM2B promotes the differentiation of basal-like breast cancer cells via the posttranslational destabilization of SLUG

Abstract

ABSTRACTKDM2B is a JmjC domain H3K36me2/H3K36me1 demethylase, which immortalizes cells in culture and contributes to the biology of both embryonic and adult stem and progenitor cells. It also functions as an oncogene that contributes to the self-renewal of breast cancer stem cells by regulating polycomb complexes. Here we show that the silencing of KDM2B results in the downregulation of SNAI2 (SLUG), SNAI1 (SNAIL) and SOX9, which also contribute to the biology of mammary stem and progenitor cells. The downregulation of these molecules is posttranscriptional and in the case of the SNAI2-encoded SLUG, it is due to calpain-dependent proteolytic degradation. Mechanistically, the latter depends on the activation of calpastatin-sensitive classical calpain(s) and on the phosphorylation-dependent inhibition of GSK3 via paracrine mechanisms. GSK3 inhibition sensitizes its target SLUG to classical calpains, which are activated by Ca2+ influx and calpastatin downregulation. The degradation of SLUG, induced by the KDM2B knockdown, promotes the differentiation of breast cancer stem cells in culture and reveals an unexpected mechanism of stem cell regulation by a histone demethylase.