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

Abstract

KDM2B 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.

A computational systems biology approach identifies SLUG as a mediator of partial Epithelial-Mesenchymal Transition (EMT)

“…The mammosphere forming potential of basal progenitor cells also decreased upon SLUG knockdown, thus the primary mammospheres generated from SLUG-KO cells were unable to give rise to secondary mammospheres, highlighting the role of SLUG on self-renewal processes in mammary gland morphogenesis [Nassour et al, 2012]. Consistent observations have been made in breast cancer and prostate cancer, where SLUG degradation promotes the differentiation of breast cancer stem cells [Fraile et al, 2020], and the basal prostate cells that expressed SLUG exhibited a partial EMT phenotype and displayed increased stemness ability [Kahonouva et al, 2020]. The functional contribution of SLUG in vitro and/or in vivo enabling stemness is also observed in human epidermal progenitor cells [Mistry et al, 2014] as well as other cancers such as glioblastoma [Chesnelong et al, 2019], hepatocellular carcinoma [Tang et al, 2016;Sun et al, 2014], colorectal cancer [Kato et al, 2020], lung cancer [Kim et al, 2020] and squamous cell carcinomas [Yu et al, 2016;Moon et al, 2020].…”

A Computational Systems Biology Approach Identifies SLUG as a Mediator of Partial Epithelial-Mesenchymal Transition (EMT)

“…The mammosphere-forming potential of basal progenitor cells also decreased upon SLUG knockdown, thus the primary mammospheres generated from SLUG-KO cells were unable to give rise to secondary mammospheres, highlighting the role of SLUG on self-renewal processes in mammary gland morphogenesis [Nassour et al, 2012]. Consistent observations have been made in breast cancer and prostate cancer, where SLUG degradation promotes the differentiation of breast cancer stem cells [Fraile et al, 2020], and the basal prostate cells that expressed SLUG exhibited a partial EMT phenotype and displayed increased stemness ability [Kahonouva et al, 2020]. The functional contribution of SLUG in vitro and/or in vivo enabling stemness is also observed in human epidermal progenitor cells [Mistry et al, 2014] as well as other cancers such as glioblastoma [Chesnelong et al, 2019], hepatocellular carcinoma [Sun et al, 2014;Tang et al, 2016], colorectal cancer [Kato et al, 2020], lung cancer [Kim et al, 2020], and squamous cell carcinomas [Yu et al, 2016;Moon et al, 2020].…”