KDM6B histone demethylase is an epigenetic regulator of estrogen receptor β expression in human pleural mesothelioma

Our plain-English summary of KDM6B histone demethylase is an epigenetic regulator of estrogen receptor β expression in human pleural mesothelioma, by A.G. Manente, G. Pinton, S. Zonca, et al (Epigenomics, 2016).

The study

• Authors: A.G. Manente, G. Pinton, S. Zonca, D. Tavian, T. Habib, P.V. Jithesh, D. Fennell, S. Nilsson, L. Moro
• Journal: Epigenomics
• Published: 2016;8(9):1227-38
• Cited by: 14 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Aim: To assess the correlation between KDM6B and estrogen receptor β (ERβ) expression in malignant pleural mesothelioma (MPM).

Materials & Methods: We evaluated gene expression by in silico analysis of microarray data, real-time PCR and western blot in MPM tumors and cell lines.

Results & Conclusion: We report a strong positive correlation between the expression of KDM6B and ERβ in MPM tumors and cell lines. We describe that, in hypoxia, the HIF2α-KDM6B axis induces an epithelioid morphology and ERβ expression in biphasic MPM cells with estrogen receptor-negative phenotype. Reduced histone H3K27 tri-methylation confirms KDM6B activity under hypoxic conditions. Importantly, cells treated during reoxygenation with the selective ERβ agonist, KB9520, maintain ERβ expression and the less aggressive phenotype acquired in hypoxia.

In plain English

This laboratory study looked at two molecules in malignant pleural mesothelioma: KDM6B, an enzyme that removes chemical marks from histone proteins, and estrogen receptor β (ERβ). It did not study asbestos exposure. Reanalyzing public gene data from 93 tumors, the authors found KDM6B among the genes more active in tumors with high activity of the ERβ gene (ESR2). In lab-grown cell lines, cells from a biphasic mesothelioma (MSTO-211H) had lower KDM6B and ESR2 than cells from an epithelioid one (REN). Raising KDM6B increased ESR2, and silencing KDM6B lowered it. When MSTO-211H cells were grown in low oxygen (1%), KDM6B and ERβ rose and the cells took on an epithelioid shape. Both changes depended on KDM6B, and the rise in KDM6B depended on HIF-2α. Returning the cells to normal oxygen reversed these changes, but adding the ERβ-activating compound KB9520 kept ERβ and the epithelioid shape. The authors concluded that a selective ERβ agonist can maintain the epithelioid phenotype during reoxygenation. They said that whether KDM6B acts directly on the ERβ gene needs further study.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study: computer (in silico) reanalysis of published tumor microarray data, plus cell-culture experiments using real-time PCR, western blot, gene silencing and overexpression, and spheroids
• Who was studied: Gene-expression data from 93 malignant pleural mesothelioma tumors in two public datasets (GSE 2549, n = 40; GSE 29354, n = 53). Also human mesothelioma cell lines: MSTO-211H (biphasic) and REN (epithelioid), with H2596 and MMP89 cells in supplementary experiments.
• Exposure: Asbestos exposure was not studied. The experimental conditions were low oxygen (1% O2, hypoxia) followed by reoxygenation, raising or silencing KDM6B and EPAS1 (HIF-2α), and treatment with the selective ERβ agonist KB9520 at 10 nM.
• Main results:
  • In the 93 tumors, KDM6B was identified among the genes upregulated in the 'high ESR2' group (false discovery rate adjusted p of 0.05 or less, fold change of 2 or more).
  • Biphasic-derived MSTO-211H cells had significantly lower ESR2 and KDM6B levels than epithelioid-derived REN cells, while EZH2 levels were equal in the two cell lines.
  • Overexpressing KDM6B in MSTO-211H cells significantly increased ESR2 mRNA and protein. Silencing KDM6B in REN cells lowered them.
  • In MSTO-211H cells grown in hypoxia, KDM6B and ERβ increased. When KDM6B was silenced, ERβ expression and H3K27 tri-methylation returned to control levels.
  • The epithelioid shape that MSTO-211H cells took on in hypoxia also depended on KDM6B.
  • Silencing EPAS1 showed that the rise in KDM6B under chronic hypoxia depended on HIF-2α.
  • After return to normal oxygen, MSTO-211H cells regained a spindle shape, and KDM6B and ERβ decreased.
  • Adding KB9520 during recovery kept the epithelioid shape and kept KDM6B, ERβ and EPAS1 expression. It also increased EP300 and HIC1 and significantly reduced SIRT1.
• The authors' conclusion: The authors concluded that a low-oxygen environment favors a change from sarcomatoid to epithelioid cell type and ERβ expression. They also concluded that targeting ERβ with a selective agonist can maintain the epithelioid phenotype during reoxygenation.
• Limitations the authors state:
  • The data do not show whether KDM6B affects ERβ promoter activity directly or indirectly; the authors said this needs additional studies.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Hypoxia, Epithelioid, Biphasic Mesothelioma.

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