Merm1 cancer target

A newly-discovered enzyme is supressed in cancer and lung inflammation and could help in the development of new drugs to target the disease. Merm1 is essential for normal functioning of glucocorticoids – hormones that regulate inflammation and energy production in cells – and is suppressed in lung inflammation and cancer. In lung cancer these hormones are known to play a role in controlling cell growth. “Glucocorticoids are central to inflammation regulation, energy metabolism, and play critical roles in cell fate decisions,” Professor David Ray, Professor of Medicine and Endocrinology at the University of Manchester told Laboratory News. “We have had a programme finding novel partner proteins for the glucocorticoid receptor (GR) with a view to seeing if these proteins may explain the observed clinical variation in glucocorticoid sensitivity.” Ray and colleagues at the Manchester Cancer Research Centre showed that Merm1 controls the binding between a glucocorticoid receptor and its target genes, an essential step for the receptor to work and to control cell growth and division. “We know that resistance to glucocorticoids happens in various inflammatory diseases, as well as cancer, in lung tissue,” said Ray. “We wanted to explore whether Merm1 was involved in this resistance and therefore involved in controlling the uncontrolled cell growth that is the hallmark of cancer.” “We found that Merm1’s mechanism of action required its enzymatic core function, and that it both facilitates recruitment of the GR to its binding sites in the genome, but also mediated some of the chromatin remodeling we see after GR binding to the genome,” he added. “Interestingly, Merm1 was found to be highly expressed in the lung, in bronchial epithelium, and so we focused our attention on lung tissue.” “Finally, we were able to show that proinflammatory cytokines, which induce glucocorticoid insensitivity, but not through reduction in GR expression, did induce degradation of Merm1 protein.  We prevented this by mutating Merm1, and rescued the cellular sensitivity to glucocorticoids. Importantly, we find loss of Merm1 in a range of human lung inflammatory, and neoplastic diseases.” Importantly, the work – published in the Journal of Biological Chemistry – revealed that inflammation, such as that seen in asthma or bronchitis, results in loss of Merm1. “This work shows that targeting Merm1 could offer a new strategy in developing anti-inflammatory treatments,” said Ray.