Selected Articles from This Issue

The interaction of ETS transcription factors and EWSR1 is associated with oncogenic function in prostate cancer and Ewing sarcoma. However, the mechanism of this pro-tumoral activity is unclear. In their study, Downing and colleagues investigated the specificity and overlap in ETS factors involved in gene fusions in Ewing sarcoma and prostate cancer. Proliferation and colony formation assays performed with EWSR1::FLI1 genetic knockdown Ewing sarcoma cells that express EWSR1::ETS fusion proteins demonstrated a rescue in colony formation ability for ETV1, ETV4, ETV5, and ERG S96E. Ewing sarcoma cells treated with EZH2 inhibitor GSK503 further showed rescue of colony formation ability in ERG expressing cells, indicating that EZH2 represses this process. Affinity pulldown revealed similar interactions between EZHZ and FOXO1 with ETS proteins, and immunoprecipitation in prostate cancer cells found an ERG/PRC2/FOXO1 complex. Pulldown of ERG in cells expressing low levels of FOXO1 also demonstrated reduced ERG/PRC2 interaction. Cells expressing high levels of AKT appeared to have depleted ERG/EZHZ interaction, while inhibition of AKT increased FOXO1. Altogether, this study shows that the ETS factors that drive Ewing sarcoma and prostate cancer are interchangeable, and that the mechanisms governing this process may be a candidate for therapeutic intervention in either malignancy.Temozolomide (TMZ) resistance is commonly developed in glioblastoma multiforme (GBM) patients, but little is known about its mechanism. In their study, Sui and colleagues identified a protein that modulates sensitivity to TMZ and evaluated the mechanism of its regulation. MTT assays using ACYP2 knockdown GBM cell lines treated with TMZ showed lower IC50 values in the knockdown compared to the control. ACYP2 knockdown cells also exhibited decreased proliferation, colony formation ability, and increased cell apoptosis upon treatment with TMZ. The opposite effect was observed upon ACYP2 overexpression in GBM cells. KEGG analysis of TCGA data further found an enrichment in differentially expressed genes associated with DNA repair pathways in patients with high expression of ACYP2. Comet tail assays and immunofluorescence staining also showed enhanced DNA damage upon ACPY2 knockdown and TMZ treatment, whereas overexpression of ACYP2 appeared to prevent DNA damage upon TMZ treatment. The authors also observed a correlation between c-Myc, a target of ACYP2, and PARP1. ChIP assays demonstrated c-Myc binding to PARP1 promoter, and dual-luciferase assays indicated c-Myc increased the transcriptional activity of the PARP1 promoter. In vivo analysis of ACYP2 knockdown also enhanced TMZ sensitivity in GBM-bearing mice, with the tumors presenting decreased levels of proliferation and growth compared to the control. Overall, this study proposes ACYP2 as a regulator of TMZ resistance and suggests that the ACYP2-driven c-Myc/PARP1 signaling axis may be targeted to remediate resistance in GBM.PTEN and SOX4, a respective tumor suppressor and transcription factor, have been clearly associated with prostate cancer progression, but the mechanism of their interaction is largely unknown. In their study, Sun and colleagues investigated the relationship between these two proteins and demonstrated their potential as therapeutic targets. Immunohistochemical staining of prostate cancer tissues revealed SOX4 and PTEN expression were inversely correlated, and that patients with SOX4+/PTEN– expression had a more aggressive phenotype, including castration-resistant prostate cancer. Further analysis in PTEN-intact prostate cancer cell lines showed that genetic manipulation of SOX4 altered PTEN protein expression but did not affect PTEN mRNA levels. A miRNA screen using TCGA and GSE data showed that the miR-106b∼25 cluster was positively correlated with SOX4 and predicted to target PTEN. Rescue experiments and dual-luciferase assays highlighted the inhibitory role of the miR-106b∼25 cluster on PTEN. Transcription factor binding databases, ChIP-qPCR, and luciferase reporter assays confirmed transcriptional regulation of the miR-106b∼25 cluster by SOX4. In vivo synergy analysis also demonstrated that SOX4 inhibition and LY294002, a small-molecule inhibitor that suppressed AKT signaling, could be combined to reduce tumor growth. Taken together, this study highlights the cooperation between SOX4 and PTEN and shows how they may be manipulated to improve patient outcomes.