Highlights of This Issue

Abstract

Epithelial ovarian cancer (EOC) remains the most lethal gynecologic malignancy in the United States. Thus, there is an urgent need to identify new targets for developing novel therapeutics for EOC. EZH2 is an epigenetic regulator that plays an important role in gene silencing. Li and colleagues showed that EZH2 is significantly overexpressed in primary human EOCs when compared with normal human ovarian surface epithelium. Moreover, loss of function analysis revealed a pivotal role of EZH2 in suppressing apoptosis and promoting proliferation and invasion of human EOC cells. There results suggest that EZH2 is a potential target for developing EOC therapeutics.Integrin α6β4 is upregulated in invasive human cancers and has been implicated in poor prognosis for cancer patients. α6β4 has been shown to enhance cancer cell function via activation of translation initiation factor eIF4E. In this study, Korneeva and colleagues found that α6β4 regulates the activity of eIF4E through Mnk1. α6β4 signals through MEK and p38 MAPK to increase in the phosphorylation and activity of Mnk1. Inhibition of Mnk1 by CGP57380 or shRNA blocks α6β4-dependent eIF4E phosphorylation and translation of VEGF mRNA. This suggests that Mnk1 could be a therapeutic target in cancers in which the α6β4 levels are high.The cellular readout of TGF-β signal is highly contextual and differs between normal and cancer cells. Using mammary epithelial cells transformed by the HER2 oncogene and a panel of breast cancer cell lines, Yu and colleagues found a contextdependent, bidirectional regulation of the DNA mismatch repair protein MSH2 as a function of TGF-β. TGF-β activated MSH2 promoter in a p53-dependent manner in nontransformed cells, whereas in transformed cells, it downregulated MSH2 expression through a miR-21-mediated mechanism. Reduced MSH2 level further resulted in tolerance to DNA-damaging chemotherapy agents in cancer cells, suggesting a role of TGF-β in inducing chemoresistance.The role of nonsteroidal anti-inflammatory drug activated Gene-1 (Nag-1) in prostate cancer is not fully determined and remains an area of interest. The data show that Nag-1 protein expression is induced by the NSAIDs R-flurbiprofen and ibuprofen downstream of NSAID induction of p75NTR, which is an established tumor suppressor and metastasis suppressor of prostate cancer cells. Induction of p75NTR decreases both survival and migration of PC-3 prostate cancer cells; however, Nag-1 induction only inhibits cell migration and not cell survival. These results suggest that Nag-1 contributes to metastasis suppressor activity but not tumor suppressor activity downstream of p75NTR.