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Histone H3K27me3 Demethylase act as Key Regulator of Stem Cell Markers in Matrix Detached Cancer Cells


 Metastasis of cancer cells requires detachment from matrix (Extra Cellular Matrix) to seed cancer cells in a distant organ. Hypoxia is prevalent in matrix detached cancer cells, are bound for metastasis. Studies have established hypoxia as chromatin modifier, as it transcriptionally controls expression of various histone demethylases (KDMs), therefore we hypothesized that hypoxia can modulate the expression of KDMs in matrix detached cancer cells. Results from our study showed that in hypoxic matrix detached cancer cells of different origins, expression and activity of KDM6B (a H3K27me3 histone demethylase) was consistently increased. Simultaneously, we found increased expression of cancer stem cells (CSCs) markers in hypoxic matrix detached cancer cells. Targeting KDM6B by using a specific inhibitor reduces the expression of CSCs markers namely SOX-2, SOX-9 and CD44 in matrix detached cancer cells. We found that KDM6B occupies the promoter region of both SOX-2 and CD44 and thereby regulate their expression. Surprisingly, we also noticed that in a feedback loop HIF1α was transcriptionally regulated by KDM6B in matrix detached cancer cells. Lastly, we observed a significant positive association between KDM6B and HIF1α in various cancer types. Overall, we found, that matrix detachment induces hypoxia, modulates epigenome to promote KDM6B activity to positively regulate expression of SOX2, CD44 and HIF1α in matrix detached conditions. We believe that KDM6B can be developed as a therapeutic target for elimination of matrix detached cancer cells, bound for metastatic events.