Abstract
Nucleotide stress induces the tumor suppressor HEXIM1 to suppress melanoma.
Major finding: Nucleotide stress induces the tumor suppressor HEXIM1 to suppress melanoma.
Mechanism: HEXIM1 inhibits oncogenic transcription elongation and stabilizes tumor suppressor transcripts.
Impact: Inducing HEXIM1-mediated antitumor cellular stress responses may be therapeutically exploited.
Cancers frequently exhibit aberrant nucleotide metabolism, which in turn affects key biological processes such as chromosomal stabilization and gene expression. RNA polymerase II (RNA Pol II)–mediated regulation of gene expression is dependent upon the release of negative transcription elongation factors by positive transcription elongation factor b (P-TEFb), resulting in the phosphorylation of RNA Pol II and subsequent transcriptional elongation. Recently, it has been shown that leflunomide-mediated inhibition of the de novo pyrimidine biosynthesis enzyme dihydroorotate dehydrogenase (DHODH) resulted in the inhibition of transcriptional elongation and decreased melanoma growth. To follow up on their DHODH findings and elucidate the mechanism by which nucleotide stress inhibits transcriptional elongation, Tan and colleagues screened the Oncomine database for the presence of candidate transcription elongation factors in melanoma and found that hexamethylene bis-acetamide inducible 1 (HEXIM1) was the only transcription elongation regulator that was differentially expressed in melanoma compared to normal controls. HEXIM1, which cooperates with 7SK snRNA to sequester P-TEFb and form a large inactive 7SK snRNP complex to prevent transcription elongation, was downregulated in melanoma tumors and cell lines. Overexpression or CRISPR-Cas9–mediated knockdown of human or fish HEXIM1 in zebrafish and of human HEXIM1 in a mouse xenograft model resulted in the suppression of melanoma tumorigenesis or quickened the onset of melanoma, respectively. Mechanistically, the stress response transcription factor SP1 upregulated HEXIM1 transcription in response to nucleotide stress, which caused concordant increased sequestration of P-TEFb by HEXIM1 to prevent transcriptional elongation of protumorigenic genes and increased binding and stabilization of antitumorigenic transcripts by HEXIM1. Together, these results identify HEXIM1 as a tumor suppressor in melanoma and show how a stress sensor can connect nucleotide metabolism and transcriptional regulation.
