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bioRxiv · 10.1101/2020.05.21.109819

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

Fraile, E.-A.·Chavdoula, E.·Laliotis, G. I.·Anastas, V.·Serebrennikova, O.·Paraskevopoulou, M. D.·Tsichlis, P. N.
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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 cells, including cancer stem cells. Here we show that the silencing of KDM2B activates a tyrosine kinase receptor-dependent paracrine mechanism, which results in the downregulation of SNAI2 (SLUG), SNAI1 (SNAIL) and SOX9, which also contribute to the biology of stem and progenitor cells. The downregulation of these molecules is posttranscriptional and in the case of SNAI2-encoded SLUG, it is due to calpain-dependent proteolytic degradation. SLUG abundance in normally growing cells is under the homeostatic control of GSK3, which phosphorylates SLUG and tags it for proteasomal degradation. The paracrine mechanism activated by KDM2B depletion, activates FGFR1 and EGFR family members, and blocks the homeostatic SLUG degradation by inactivating GSK3. This, however, sensitizes SLUG to classical calpains, which are also activated in KDM2B-depleted cells via Ca2+ influx and calpastatin downregulation. The switch in SLUG degradation pathways, results in the rapid degradation of SLUG and the differentiation of breast cancer stem cells, revealing an unexpected mechanism of stem cell regulation by a lysine demethylase. HIGHLIGHTSO_LIGSK3 phosphorylates SLUG and promotes its homeostatic proteasomal degradation C_LIO_LIKDM2B depletion results in GSK3 inactivation, Ca2+ upregulation and calpain activation. C_LIO_LIDownregulation of SLUG phosphorylation by GSK3, sensitizes SLUG to calpain activation. C_LIO_LIGSK3 inactivation and Ca2+ upregulation are due to an RTK-dependent paracrine mechanism C_LI O_FIG O_LINKSMALLFIG WIDTH=199 HEIGHT=200 SRC="FIGDIR/small/109819v2_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@1cee15corg.highwire.dtl.DTLVardef@12d757corg.highwire.dtl.DTLVardef@17c2dd4org.highwire.dtl.DTLVardef@1a4dcef_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Fraile, E.-A., Chavdoula, E., Laliotis, G. I., Anastas, V., Serebrennikova, O., Paraskevopoulou, M. D., Tsichlis, P. N.. 2020-05-25. The inhibition of KDM2B promotes the differentiation of basal-like breast cancer cells via the posttranslational destabilization of SLUG.. https://doi.org/10.1101/2020.05.21.109819

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