Highlights of This Issue

CHCHD2 encodes a coiled-coil helix coiled-coil helix domain-containing protein that maps close to EGFR, and it is recurrently coamplified in non–small cell lung cancer (NSCLC), which accounts for more deaths per year than any other cancer. CHCHD2 protein is consistently upregulated in NSCLC, and its knockdown impairs cell proliferation, migration, and mitochondrial respiration. CHCHD2 is predominantly mitochondrial, and it is required for the stable assembly of oxidative phosphorylation components. The CHCHD2 interactome also includes an oncogenic transcription factor. Hence, CHCHD2 appears to function through mitochondrial and nuclear interactions, and, along with EGFR, appears to be a driver of 7p11.2 amplification and the cancer phenotype.

Anticancer drugs targeting microtubule dynamics are widely prescribed for a broad range of cancers. However, drug resistance and severe side effects in treated patients limit their effectiveness. Lindström and colleagues show that citral dimethyl acetal (CDA), a citral analogue that specifically targets the nuclear activity of γ-tubulin, is a member of the tubulin family but has no effect on microtubule dynamics. CDA kills tumor cells with an impaired retinoblastoma (RB1) tumor suppressor signaling pathway without affecting healthy cells. CDA's in vivo antitumorigenic activity paves the way for the development of a novel broad-range, targeted anticancer therapy that causes fewer side effects.

Transglutaminase-2 (TG2) is a vital cross-linking enzyme in the tumor microenvironment that has been linked to cancer progression, but its precise role appears to be context dependent. Cellura and colleagues found that TG2 inhibits invasion of colorectal cancer cells in vitro. Using a cell model of metastasis and analysis in sections taken from patients, a novel mechanism is described by which TG2 is downregulated in advanced colorectal cancer. Amplification of chromosome 13 leads to enhanced levels of miR-19 in metastatic cells, inhibiting TG2 to promote invasion. This study provides an important link between chromosomal instability, miRNA expression, and TG2 status, with functional effects on colorectal cancer cell behavior.

The hypermethylated in cancer 1 (HIC1) gene encodes a sequence-specific transcriptional repressor that is frequently silenced in many solid tumors. Janeckova and colleagues used a conditional knock-out of Hic1 to identify genes regulated by this repressor. Hic1 ablation in primary fibroblasts and intestinal epithelia resulted in upregulation of Toll-like receptor 2 (TLR2), a critical mediator of prosurvival signal transduction pathways. In chemically induced colon cancer, Hic1 loss caused formation of highly proliferative Tlr2-positive neoplastic lesions. This study reveals that the tumor-suppressive function of Hic1 is related to its inhibitory action on signaling mediated by the Tlr2 receptor present on tumor cells.