The Histone H3K27me3 Demethylases KDM6A/B Resist Anoikis and Transcriptionally Regulate Stemness-Related Genes

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.

Loss of OVOL2 in Triple‐Negative Breast Cancer Promotes Fatty Acid Oxidation Fueling Stemness Characteristics

“…The sphere‐forming assay creates a relatively deprived environment for cells and assesses their stemness based on their resistance to anoikis, a form of programmed cell death induced by detachment from the extracellular matrix. [ 42 ] On the other hand, the in vivo tumor transplantation assay directly evaluates the tumor‐initiating capability of cancer cells, serving as a measure of their stemness. [ 43 ] Through these assessments, we made an intriguing observation that OVOL2 not only possesses the ability to inhibit sphere formation and tumor‐initiating capacity in cells cultured in vitro but also exerts a significant impact on the stemness characteristics of breast tumor cells in the PyVT mouse model.…”

Transcriptional co-activators: emerging roles in signaling pathways and potential therapeutic targets for diseases

“… 540 Another lysine demethylase KDM6B has been reported to enhance stemness related genes like SOX2, SOX9, and OCT4. 541 Li et al 542 identified JMJD3 as one of the main drivers of esophageal squamous cell carcinoma pathogenesis through JMJD3/MYC/miR-17–92 pathway and regulate stemness and sensitivity to therapy. Steroid receptor co-activator 1 and 3 (SRC1/3) plays a crucial role in CSC state maintenance and metastasis in breast cancer cell lines.…”

MicroRNA-Mediated Regulation of Histone-Modifying Enzymes in Cancer: Mechanisms and Therapeutic Implications

“…The decrease in KDM6A activity leads to the maintenance of strong methyl groups on histone H3K27, which in turn affects the maintenance of condensed chromatin in gene regions responsible for stem cell differentiation. This may result in the inhibition of the expression of differentiation genes and promote the maintenance of cells in an undifferentiated state [353][354][355]. In breast cancer, miR-486 overexpression has been associated with maintaining cells in an undifferentiated state.…”