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The Histone H3K27me3 Demethylases KDM6A/B Resist Anoikis and Transcriptionally Regulate Stemness-Related Genes
Mohammed Razeeth Shait Mohammed1,2, Mazin Zamzami1, Hani Choudhry1,2
1Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia.
Abstract:
Epithelial cancer cells that lose attachment from the extracellular matrix (ECM) to seed in a distant organ often undergo anoikis's specialized form of apoptosis. Recently, KDM3A (H3K9 demethylase) has been identified as a critical effector of anoikis in cancer cells. However, whether other histone demethylases are involved in promoting or resisting anoikis remains elusive. We screened the major histone demethylases and found that both H3K27 histone demethylases, namely, KDM6A/B were highly expressed during ECM detachment. Inhibition of the KDM6A/B activity by using a specific inhibitor results in reduced sphere formation capacity and increased apoptosis. Knockout of KDM6B leads to the loss of stem cell properties in solitary cells. Furthermore, we found that KDM6B maintains stemness by transcriptionally regulating the expression of stemness genes SOX2, SOX9, and CD44 in detached cells. KDM6B occupies the promoter region of both SOX2 and CD44 to regulate their expression epigenetically. We also noticed an increased occupancy of the HIF1α promoter by KDM6B, suggesting its regulatory role in maintaining hypoxia in detached cancer cells. This observation was further strengthened as we found a significant positive association in the expression of both KDM6B and HIF1α in various cancer types. Overall, our results reveal a novel transcriptional program that regulates resistance against anoikis and maintains stemness-like properties.
Insights
Histone demethylases KDM6A/B promote cancer cell survival during anoikis by maintaining stemness. KDM6B regulates stemness genes and hypoxia, revealing a new survival pathway.
Area of Science:
- Cancer Biology
- Epigenetics
- Cell Death
Background:
- Anoikis, a form of apoptosis, eliminates detached epithelial cancer cells.
- KDM3A is a known effector of anoikis, but other histone demethylases' roles are unclear.
- Understanding anoikis resistance is crucial for cancer metastasis research.
Purpose of the Study:
- To investigate the role of other histone demethylases in anoikis.
- To identify novel regulators of anoikis resistance and cancer stemness.
Main Methods:
- Screening of major histone demethylases in detached cancer cells.
- Inhibition and knockout studies of KDM6A/B.
- Analysis of stemness gene expression (SOX2, SOX9, CD44) and HIF1α promoter occupancy.
- Correlation analysis of KDM6B and HIF1α expression in various cancer types.
Main Results:
- KDM6A/B were highly expressed during ECM detachment.
- KDM6A/B inhibition increased apoptosis and reduced sphere formation.
- KDM6B knockout diminished stem cell properties; KDM6B regulates SOX2, SOX9, CD44, and HIF1α expression epigenetically.
- KDM6B occupancy of HIF1α promoter suggests a role in maintaining hypoxia.
- Positive association between KDM6B and HIF1α expression across cancer types.
Conclusions:
- KDM6A/B are novel regulators promoting anoikis resistance in epithelial cancer cells.
- KDM6B maintains cancer stemness by epigenetically regulating key stemness genes and promoting hypoxia via HIF1α.
- This study uncovers a new transcriptional program critical for anoikis resistance and stemness maintenance.
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