GSE132624
MITF controls the TCA cycle to modulate the melanoma hypoxia response
In response to the dynamic intra-tumor microenvironment, melanoma cells adopt different phenotypic states possessing distinct biological properties associated with differential expression of the microphthalmia-associated transcription factor (MITF). The response to hypoxia, a major microenvironmental cue, is underpinned by expression of hypoxia-inducible transcription factors (HIFs) that reprogram metabolism and promote pro-angiogenic VEGF expression. HIF1? indirectly represses MITF via the transcription factor bHLHE40/DEC1, and MITF can activate HIF1? expression. Although HIF and MITF share a highly related DNA-binding specificity, it is unclear whether they share a subset of target genes. Moreover, the genome-wide impact of hypoxia on melanoma, which genes are direct HIF targets, and whether melanoma cell lines representing different phenotypic states exhibit distinct hypoxic responses is unknown. Here we show, that three different melanoma cell lines exhibit widely different hypoxia responses with only a core 23 genes regulated in common after 12 h in hypoxia. Surprisingly, under hypoxia MITF is transiently up-regulated by HIF1? and co-regulates a subset of HIF targets including VEGFA. Significantly, we also show that MITF represses itself and also regulates SDHB to control the TCA cycle and suppress pseudo-hypoxia. Our results reveal a previously unsuspected role for MITF in metabolism and the network of factors underpinning the hypoxic response in melanoma. Overall design: Melanoma cell lines representing 3 phenotypically distinct states were subjected to time-course hypoxia treatment for transcriptomic analysis