Understanding the role of MITF in hypoxia

One challenge in the treatment of cancer, including melanoma, is the different responses of cells within a tumour to therapy, which can lead to resistance. This so-called heterogeneity is caused by individual cells experiencing distinct microenvironmental signals and can be studied in the lab using cancer cell lines made from different tumours. In melanoma, MITF is a key regulator of the response to the microenvironment and promotes cell proliferation over invasiveness. A particularly relevant microenvironmental cue is low oxygen levels – hypoxia – found in tumours that activate the key regulator HIF (hypoxia inducible factor) to alter cellular metabolism. In this article published in Pigment Cell and Melanoma Research, Pakavarin Louphrasitthiphol and colleagues from Prof. Colin Goding’s lab characterise the interplay between hypoxia and MITF. Contrary to previous findings, MITF is transiently activated by HIF upon hypoxia. MITF co-regulates a subset of hypoxia response genes with HIF and alters cellular metabolism to suppress pseudo-hypoxia. By studying a range of melanoma cell lines, the authors demonstrate a large variation in hypoxic response. This work has implications for the understanding of intra-tumour heterogeneity in response to low oxygen and the efficacy of cancer treatments.