Highlights of This Issue

Abstract

Melanomas display a high degree of heterogeneity even within an individual lesion. Heterogeneity may be driven by reversible events that dynamically control gene expression profiles. Weiss and colleagues describe the interplay between two transcription factors, FOXD3 and TWIST1, which are regulated in an opposite manner by MEK–ERK signaling in mutant BRAF melanoma. ChIP-seq analysis and validation studies show that FOXD3 directly binds to the TWIST1 locus and negatively regulates TWIST1 expression. Furthermore, TWIST1 expression counteracts impaired melanoma cell migration induced by FOXD3. These findings imply that the interplay between these transcription factors reprograms melanoma cells between states with different metastatic properties.Allosteric inhibitors of mTORC1 (rapalogs) show modest clinical efficacy, as they also block feedback inhibition of the upstream PI3K signaling pathway. Sharma and colleagues found acquired resistance to fludarabine (Flu), an antipurine indicated for chronic lymphocytic leukemia (CLL), to be associated with hyperactivated mTORC1. To bypass the limitations of rapalogs, downstream metabolic consequences of mTORC1 activation were examined to identify druggable targets. Activation of mTORC1, via phospho-CAD, promoted de novo pyrimidine biosynthesis and resulted in addiction to mitochondrial respiration in Flu-resistant cells. This study identifies mitochondrial respiration and de novo pyrimidine biosynthesis as potential therapeutic targets in mTORC1-dependent cancer settings, such as Flu-resistant CLL.The hypoxia-inducible factor (HIF)–mediated transcriptional response plays a critical role in solid tumor progression. However, it is unclear if HIF promotes tumor progression by increasing a single or multiple RNA isoforms from each HIF target gene because individual HIF target genes often express many RNA transcripts. In this study, Sena and colleagues analyzed the hypoxia response at the RNA isoform level and found that HIF promotes fully spliced isoforms of HIF target genes. This genome-wide study uncovers a novel function of HIF in regulating RNA splicing of HIF target genes and provides evidence that RNA splicing is not a “housekeeping” process, but is actively regulated.β-catenin is a well-established coactivator of Wnt-mediated gene expression. Sirtuin 2 (SIRT2) is a NAD-dependent protein deacetylase that has been shown to play a major role in metabolism and longevity. Nguyen and colleagues demonstrate that SIRT2 directly interacts with β-catenin to regulate the expression of Wnt target genes, and the interaction can be modulated by oxidative stress. These findings provide mechanistic insight into SIRT2 as a potentiator of the radiation-induced DNA damage response and suggest that disruption of the SIRT2/β-catenin interaction may be a therapeutic target to preserve the integrity of aging cells against exogenous stressors such as ionizing radiation.