Highlights of This Issue

Abstract

Epigenetic events like methylation are critically important to normal tissue homeostasis. As such, epigenetic changes often occur during tumorigenesis. Jumonji domain-containing protein 3 (JMJD3) demethylates tri- and dimethylated histone H3 at lysine 27 (H3K27) and is central in controlling the chromatin state as well as numerous biologic programs such as cellular senescence. Here, Perrigue and colleagues assessed the status of JMJD3 in the context of glioma and found intrinsic differences that reflected both phenotypes and variations associated with senescence. Mechanistic study demonstrated that JMJD3 activated the senescence-associated secretory phenotype (SASP) and, based on RNA-seq analysis, regulated cancer-related and inflammatory-related transcripts. Combined, the epigenetic reprogramming and secretory phenotype induced by JMJD3 may stimulate homing of nearby cells in the tumor microenvironment to the tumor.Little is known about the molecular drivers of phyllodes tumors, which are rare stromal breast tumors with malignant potential. In the current Rapid Impact article, Cani and colleagues report on a study in which they performed next-generation sequencing on routine clinical specimens to shed light on the mutational and copy number alteration landscape of phyllodes tumors. Importantly, MED12, a RNA polymerase II transcriptional machinery component that has been reported in other estrogen-driven stromal tumors, was mutated with high frequency, suggesting a candidate driver. Phyllodes tumors with aggressive behavior were characterized by additional alterations in tumor suppressors and oncogenes, including a high level of EGFR and IGF1R amplifications, presenting opportunities for targeted therapy.To date, there are no effective treatments for metastatic prostate cancer, and a better understanding of the metastatic process is urgently needed. Lymphoid enhancer-binding factor-1 (LEF1) modulates epithelial–mesenchymal transition (EMT), promoting invasive ability in cancer cells and metastasis. Liang and colleagues integrated miRNA microarray, luciferase, and chromatin immunoprecipitation (ChIP) analyses to identify that miR-34a directly and negatively targets LEF1 and its effects on EMT, reducing cell migration and invasion. Consistently, miR-34a is also significantly downregulated in human prostate cancer specimens. Together, these results indicate that the miR-34a/LEF1 axis is a potential molecular target for novel therapeutic strategies in prostate cancer.EGFR is often mutated in various cancers and therefore is an important therapeutic target. Erlotinib and gefitinib are FDA- approved drugs targeting EGFR. Understanding differences in autophosphorylation kinetics and drug sensitivity between wild- type and oncogenic EGFR signaling is important for correlating specific phosphorylation signatures to drug responsiveness. By comparing drug responsiveness in wild-type and oncogenic EGFR expressing cells, Kim and colleagues observed dramatic differences in potency of these drugs for inhibiting downstream effectors, Cbl and STAT5. This study provides a new understanding of the EGFR signaling environment and reveals useful paradigms for predicting patient response to EGFR targeted therapy as well as combination treatments.