Stress from Nucleotide Depletion Activates the Transcriptional Regulator HEXIM1 to Suppress Melanoma

Abstract

Summary Studying cancer metabolism gives insight into tumorigenic survival mechanisms and susceptibilities. In melanoma, we identify HEXIM1, a transcription elongation regulator, as a melanoma tumor suppressor that responds to nucleotide stress. HEXIM1 expression is low in melanoma. Its overexpression in a zebrafish melanoma model suppresses cancer formation while its inactivation accelerates tumor onset in vivo. Knockdown of HEXIM1 rescues zebrafish neural crest defects and human melanoma proliferation defects that arise from nucleotide depletion. Under nucleotide stress, HEXIM1 is induced to form an inhibitory complex with P-TEFb, the kinase that initiates transcription elongation, to inhibit elongation at tumorigenic genes. The resulting alteration in gene expression also causes anti-tumorigenic RNAs to bind to and be stabilized by HEXIM1. HEXIM1 plays an important role in inhibiting cancer cell-specific gene transcription while also facilitating anti-cancer gene expression. Our study reveals an important role for HEXIM1 in coupling nucleotide metabolism with transcriptional regulation in melanoma.

P-TEFb activation by RBM7 shapes a pro-survival transcriptional response to genotoxic stress

“…Finally, P-TEFb-dependent Pol II pause release is frequently dysregulated in cancers, particularly in those addicted to c-MYC and translocations of mixed-lineage leukemia gene (Dawson et al, 2011;Delmore et al, 2011;Huang et al, 2014;Ji et al, 2014;Luo et al, 2012;Rahl et al, 2010;Tan et al), spurring interest in the development of highly specific CDK9 inhibitors for clinical use (Lu et al, 2015;Olson et al, 2018). Our discovery of the prosurvival role of P-TEFb in genotoxic stress reinforces the relevance of this critical transcriptional kinase to cancer biology.…”

The metabolic programming of stem cells

“…Gly decarboxylase enzyme (Gldc), which is also highly up-regulated in PSCs, uses Gly to generate folate intermediates to fuel one-carbon metabolism (Zhang et al 2012). The folate intermediates fuel nucleotide synthesis and the rapid proliferation rate of PSCs as well as neural crest progenitors (Wang et al 2009;Tan et al 2016). However, the specificity of Thr deprivation to PSCs and not just any proliferative cell type also suggests that the metabolites resulting from Thr-Gly degradation might be used specifically for self-renewal of the pluripotent state.…”

From fish bowl to bedside: The power of zebrafish to unravel melanoma pathogenesis and discover new therapeutics

“…Others have since identified the 1q21 interval as a novel melanoma‐susceptibility locus for familial melanoma (Macgregor et al., ), solidifying the idea that SETDB1 is a bona fide oncogene in human melanoma. The MiniCoopR expression system has been used by various studies to functionally test specific putative modifiers of melanoma (Kaufman et al., ; Tan et al., ), and validate loss of 5‐hydroxyl‐methylcytosine (5‐hmC) as an epigenetic hallmark of melanoma (Lian et al., ). It has also been employed as a discovery tool to identify new epigenetic regulators of metastatic melanoma (E. van Rooijen, unpublished).…”