KAT5 (Tip60) is a potential therapeutic target in malignant pleural mesothelioma

Our plain-English summary of KAT5 (Tip60) is a potential therapeutic target in malignant pleural mesothelioma, by S. Cregan, L. McDonagh, Y. Gao, et al (International Journal of Oncology, 2016).

The study

• Authors: S. Cregan, L. McDonagh, Y. Gao, M.P. Barr, K.J. O'Byrne, S.P. Finn, S. Cuffe, S.G. Gray
• Journal: International Journal of Oncology
• Published: 2016;48(3):1290-6
• Cited by: 29 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant pleural mesothelioma (MPM) is a rare aggressive cancer of the pleura. Asbestos exposure (through inhalation) is the most well established risk factor for mesothelioma. 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. Lysine acetyltransferases (KATs) including KAT5 have been linked with the development of cisplatin resistance. This gene may therefore be altered in MPM and could represent a novel candidate target for intervention. Using RT-PCR screening the expression of all known KAT5 variants was found to be markedly increased in malignant tumors compared to benign pleura. When separated according to histological subtype, KAT5 was significantly overexpressed in both the sarcomatoid and biphasic subgroups for all transcript variants. A panel of MPM cell lines including the normal pleural cells LP9 and Met5A was screened for expression of KAT5 variants. Treatment of cells with a small molecule inhibitor of KAT5 (MG-149) caused significant inhibition of cellular proliferation (p<0.0001), induction of apoptosis and was accompanied by significant induction of pro-inflammatory cytokines/chemokines.

In plain English

This laboratory study looked at a protein called KAT5 (also known as Tip60) in malignant pleural mesothelioma. The authors measured KAT5 gene activity (mRNA) in two sets of samples. The first was tumor tissue from 17 patients with malignant pleural mesothelioma, taken during surgery at Glenfield Hospital in Leicester, UK. The second was 5 benign samples from people never diagnosed with the disease. All four known forms of KAT5 were significantly higher in the tumors than in the benign tissue, and the greatest increase was in the biphasic tumor type. The authors then treated mesothelioma cells grown in the laboratory with MG 149, an experimental drug that blocks KAT5. At concentrations above 10 micromolar it significantly reduced cell growth in two cell lines. At 2.5 or 5 micromolar it significantly increased cell death in one line. It also increased the expression of several inflammation-related genes. The study did not examine asbestos exposure. The authors concluded that KAT5 may be a new treatment target. They cautioned that, because the drug induced these inflammation-related molecules, it might cause cytokine response syndrome if used as a therapy.

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: measurement of KAT5 mRNA in surgical tumor samples and benign pleura, plus experiments on cultured mesothelioma cell lines treated with a KAT5 inhibitor (MG 149)
• Who was studied: 17 malignant pleural mesothelioma tumor samples (7 epithelioid, 6 biphasic, 4 sarcomatoid) from patients who had extended pleuro-pneumonectomy at Glenfield Hospital, Leicester, UK, and 5 benign samples from patients never diagnosed with mesothelioma. Also a panel of laboratory cell lines, including the normal lines LP9 and Met5A. Drug tests used the REN and NCI-H226 lines. No dates given.
• Exposure: Asbestos exposure was not studied. The experimental exposure was the KAT5 inhibitor MG 149, applied to cultured cells. Proliferation tests used 1, 5, 10, 15, 20 and 25 micromolar for 24 hours.
• Main results:
  • All four KAT5 variants were expressed at significantly higher levels in the 17 mesothelioma tumor samples than in benign pleura.
  • When tumors were grouped by histological subtype, the largest increase was in the biphasic subtype.
  • All cell lines tested expressed KAT5. Basal levels were higher mainly in the mesothelioma lines and low in the normal LP9 line.
  • At concentrations above 10 micromolar, MG 149 significantly reduced the growth rate of both cell lines tested (REN and NCI-H226).
  • In NCI-H226 cells, 2.5 or 5 micromolar MG 149 significantly increased programmed cell death (apoptosis) at 24 and 48 hours, along with increased caspase-3/7 activation.
  • MG 149 (15 micromolar for 24 hours) increased gene expression of several pro-inflammatory chemokines, measured by RT-PCR. Quantitative PCR confirmed increased expression of CXCL1 and CXCL8 and found a small but significant decrease in CXCL13 expression.
• The authors' conclusion: The authors concluded that KAT5 may be a new treatment target in malignant pleural mesothelioma.
• Limitations the authors state:
  • The authors noted that because MG 149 induced pro-inflammatory cytokines and chemokines, it might trigger cytokine response syndrome if used as a therapy.
  • The authors noted a further caveat. Earlier research found that IL-8, whose expression MG 149 increased, promotes blood vessel growth and acts as a growth factor in mesothelioma.
  • The authors stated that future studies should examine whether KAT5 levels relate to patient outcome.

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, Asbestos Exposure, Mesothelioma, Cisplatin, Pemetrexed (Alimta), Raltitrexed, Histological Subtype.

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• CD30 is a potential therapeutic target in malignant mesothelioma — S. Dabir, A. Kresak, et al. (2015)
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• CD157: From immunoregulatory protein to potential therapeutic target — E. Ortolan, S. Augeri, et al. (2019)

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