Kdm6a and Kdm6b: Altered expression in malignant pleural mesothelioma

Our plain-English summary of Kdm6a and Kdm6b: Altered expression in malignant pleural mesothelioma, by S. Cregan, M. Breslin, G. Roche, et al (International Journal of Oncology, 2017).

The study

• Authors: S. Cregan, M. Breslin, G. Roche, S. Wennstedt, L. MacDonagh, C. Albadri, Y. Gao, K.J. O'Byrne, S. Cuffe, S.P. Finn, S.G. Gray
• Journal: International Journal of Oncology
• Published: 2017;50(3):1044-1052
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant pleural mesothelioma (MPM) is a rare aggressive cancer of the pleura primarily associated with prior exposure to asbestos. The current standard of care for patients suffering from MPM is a combination of cisplatin and pemetrexed (or alternatively cisplatin and raltitrexed). Most patients, however, die within 24 months of diagnosis. New therapies are therefore urgently required for this disease. Inflammation is thought to be a key element in the pathogenesis of MPM, and recently Kdm6 family members (Kdm6a and Kdm6b) have been identified as playing important roles in inflammatory processes. As such these genes could potentially represent novel candidate targets for intervention in MPM. Using RT-PCR we examined the expression of Kdm6aA and Kdm6b in a panel of MPM cell lines and in a cohort of snap-frozen patient samples isolated at surgery comprising benign, epithelial, biphasic and sarcomatoid histologies. Both Kdm6a and Kdm6b were found to be significantly overexpressed in MPM at the mRNA level. However, tests examining if targeting therapeutically Kdm6a/b using a specific small molecule inhibitor (GSK-J4) was potentially useful for treating MPM, revealed that anti-proliferative activity was higher at lower drug concentrations in cell lines derived from normal mesothelial cells compared to those derived from malignant cells. Treatments with GSK-J4 were found to be associated with the induction of apoptosis and increased expression of pro-inflammatory cytokines. As such our results demonstrate that whilst members of the Kdm6 family are overexpressed in MPM they may not be suitable candidates for therapy and may elicit a cytokine storm.

In plain English

This laboratory study examined two genes, Kdm6a and Kdm6b, in malignant pleural mesothelioma (MPM). It did not study asbestos exposure. The authors measured the genes' mRNA levels in a panel of cell lines and in surgical samples from Leicester, UK: 5 benign lesions and 17 MPM tumors. One figure gives the benign group as 4 or 5. Both genes were found in all cell lines. Both were significantly higher in MPM tumors than in benign pleura (P=0.0036 for Kdm6a, P=0.0122 for Kdm6b). In one public dataset, only Kdm6a was significantly raised. GSK-J4 is an experimental compound that inhibits the enzymes made by these genes. It slowed the growth of two MPM cell lines. In one of those lines it also raised the mRNA levels of three inflammatory signalling molecules. A normal mesothelial cell line was more sensitive to the compound and showed more cell death. The authors concluded that the genes may be a treatment target, but that possible harm to normal pleura or a 'cytokine storm' means further studies are needed. They said their sample was too small to compare tumor subtypes.

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: mRNA levels measured in cell lines and surgical tumor samples, analysis of public datasets, and experiments testing an inhibitor compound on cells in culture
• Who was studied: Surgical samples from patients at Glenfield Hospital, Leicester, UK: 5 benign lesions and 17 MPM tumors (7 epithelioid, 4 sarcomatoid, 6 biphasic). The Figure 2 legend gives the benign group in the mRNA comparison as 4 or 5. The study also used a panel of cell lines: the normal mesothelial lines LP9 and Met5A, and malignant MPM lines.
• Exposure: No asbestos exposure was studied, and the patients' exposure histories are not reported. The exposure tested was the Kdm6 inhibitor GSK-J4 (and GSK-J1), applied to cells.
• Main results:
  • Kdm6a and Kdm6b mRNA were detectable in all cell lines tested, normal and malignant.
  • In patient samples, Kdm6a mRNA (P=0.0036) and Kdm6b mRNA (P=0.0122) were significantly higher in MPM tumors than in normal pleura.
  • By tumor subtype, Kdm6b mRNA was significantly altered only in the biphasic subtype.
  • In the public Gordon et al dataset, Kdm6a was significantly higher in MPM than in benign pleura or lung (P=0.007). Kdm6b was not significantly altered.
  • In a TCGA mesothelioma dataset of 87 samples, overexpression of Kdm6a and Kdm6b was seen in a small group of patients.
  • GSK-J4, the cell-active form of a selective inhibitor of Kdm6a and Kdm6b, inhibited cell proliferation in the two MPM cell lines tested (NCI-H226 and REN).
  • In NCI-H226 MPM cells, GSK-J4 significantly increased the mRNA levels (measured by RT-PCR) of the pro-inflammatory molecules CXCL1 (P=0.0072), CXCL2 (P=0.004) and CXCL8/IL-8 (P=0.0038).
  • The normal mesothelial cell line LP-9 was more sensitive to GSK-J4 than the MPM cell lines NCI-H226 and REN.
  • After GSK-J4 treatment, the normal cell line showed more apoptosis (programmed cell death) than the MPM cell lines.
• The authors' conclusion: The authors concluded that the Kdm6 family may be a new treatment target in MPM. Because of possible damage to normal pleura or a possible cytokine storm, they said further studies are needed. The abstract states more firmly that these genes may not be suitable candidates for therapy.
• Limitations the authors state:
  • The sample was too small to compare tumor subtypes, and a larger sample is needed.
  • The benign comparison samples were inflamed. Normal pleura from lung cancer patients might have been a more suitable control.
  • Normal cells were more sensitive to the compound in culture, yet patient tumors had much higher Kdm6 levels than normal pleura. The authors say this discrepancy remains to be resolved.

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, Pleura, Cisplatin, Pemetrexed (Alimta), Raltitrexed, Inflammation, Biphasic Mesothelioma, Sarcomatoid.

Related studies

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• KDM6B histone demethylase is an epigenetic regulator of estrogen receptor β expression in human pleural mesothelioma — A.G. Manente, G. Pinton, et al. (2016)
• Not so WEE: targeting G₂/M to kill mesothelioma cells — P. Dent (2014)
• KAT5 (Tip60) is a potential therapeutic target in malignant pleural mesothelioma — S. Cregan, L. McDonagh, et al. (2016)
• Gli as a novel therapeutic target in malignant pleural mesothelioma — H. Li, N. Lui, et al. (2013)
• Essential role of the histone lysine demethylase KDM4A in the biology of malignant pleural mesothelioma (MPM) — M. Lapidot, A.E. Case, et al. (2021)

Browse more research in International Journal of Oncology, or return to medical research.