HEXIM1 is induced by DHODH inhibition to suppress melanoma [ChIP-Seq]. Homo sapiens

Recent evidence suggests that leflunomide, a DHODH inhibitor, disrupts neural crest development and melanoma pathogenesis via inhibiting transcription elongation. Here, we provide evidence that a transcriptional regulator, HEXIM1, is upregulated in response to leflunomide. HEXIM1 is assembled into the 7SK snRNP complex to sequester and inhibit the kinase P-TEFb. P-TEFb triggers elongation by phosphorylating RNA polymerase II and pausing factors. Knockdown of hexim in zebrafish rescues the effects of leflunomide. HEXIM1 expression is low in human melanoma. In addition, HEXIM1 overexpression can suppress melanoma onset in zebrafish. Increased HEXIM1 expression, in response to low nucleotides triggered by DHODH inhibition, sequesters P-TEFb away from melanoma pathogenesis, proliferation and cell cycle genes based on GRO-seq and ChIP-seq analyses. This reduces productive elongation at genes that maintain the tumorigenic state. Our study illustrates that HEXIM1 is a tumor suppressor that responds to cell stress, consequently inhibiting productive elongation of proliferative genes in melanoma. Overall design: ChIP-seq analysis of HEXIM1 and CDK9 chromatin binding in human A375 melanoma cells treated with either DMSO or 25uM A771726 for 48 hrs.