Summary The transcriptional co-activator YAP plays an important role in organ size control and tumorigenesis. However, how Yap gene expression is regulated remains unknown. This study shows that the Ets family member GABP binds to the Yap promoter and activates YAP transcription. The depletion of GABP downregulates YAP, resulting in a G1/S cell cycle block and increased cell death, both of which are substantially rescued by reconstituting YAP. GABP can be inactivated by oxidative mechanisms, and acetaminophen-induced GSH depletion inhibits GABP transcriptional activity and depletes YAP. In contrast, activating YAP by deleting Mst1/Mst2 strongly protects acetaminophen-induced liver injury. Similar to its effects on YAP, the Hippo signaling inhibits GABP transcriptional activity through several mechanisms. In human liver cancers, enhanced YAP expression is correlated with increased nuclear expression of GABP. Therefore, we conclude that GABP is an activator of Yap gene expression and a potential therapeutic target for cancers driven by YAP.

MUC16/CA125 has been identified as a prominent cancer biomarker, especially for epithelial ovarian cancers, in clinical test for over three decades. Due to its huge mass, limited knowledge of MUC16 was acquired previously. By utilizing a well characterized self-made MUC16 monoclonal antibody, we identified the endogenous interaction between a C-terminal fragment of MUC16 (MUC16C) and β-catenin for the first time, and further elucidated that trans-activation domain of β-catenin is required for this interaction. Such interaction could activate the Wnt/β-catenin signaling pathway by facilitating cytosol-nucleus transportation of β-catenin, consequently induce cell proliferation and the migration, eventually lead to tumorigenesis and metastasis in nude mice. Consistently, knockdown of MUC16 significantly weakened the capabilities of cells for proliferation and migration. Based on our discovery, we suggest that MUC16 appears as an attractive target for the development of effective anticancer drugs.

Two hallmarks of cancer cells are their resistance to apoptosis and ability to thrive despite reduced levels of vital serum components. c-jun N-terminal kinase (JNK) activation is crucial for apoptosis triggered by serum starvation (SS), and isocitrate dehydrogenase 1 (IDH1) mutations are tumorigenic, in part, because they produce the abnormal metabolite 2-hydroxyglutarate (2-HG). However, it is unknown whether 2-HG-induced tumorigenesis is partially due to JNK inhibition and thus defective SS-induced apoptosis. We show here, using IDH1-R132Q knockin mutant mouse cells, that 2-HG inhibits JNK activation induced only by SS and not by UV or doxorubicin, and thus can block apoptosis. Upon SS, Cdc42 normally disrupts mixed lineage kinase 3's (MLK3's) auto-inhibition, triggering the MLK3-MKK4/7-JNK-Bim apoptotic cascade. 2-HG binds to Cdc42 and abolishes its association with MLK3, inactivating MLK3 and apoptosis. Allograft tumor assays in mice demonstrate that this mechanism contributes to tumorigenesis driven by mutant IDH1, a result confirmed by detection of JNK inactivation in human gliomas harboring IDH1-R132H mutations.

High abundance proteins (HAP) were often removed from crude serum sample when finding biomarkers of diagnosing cancers, however, it will surely filtrate many potential biomarkers bound to HAP. In order to enable the detection of these potential biomarkers, saving the HAP will be of great significance for finding more biomarkers. Here, a serum proteomics technology was developed for finding biomarkers of liver-cancer from crude human serum without depletion of HAP. The crude human serum (CHS) was dispersed in a lysis buffer that has capacities for improving the protein resolution, and then separated with two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) for proteomic analysis. The differentially expressed proteins from Crude male serum (CMS) compared to crude serum of male patient with liver cancer (LCMPCS) were found and identified by a combined off-line approach of 2D-PAGE and matrix-assisted laser desorption/ ionization-time of flight mass spectrometry (MALDI-TOF). Approximately 800 protein spots on a 2D-PAGE gel were detected by Melanie 4 software from samples both CMS and LCMPCS in the present of the lysis buffer. Significantly different expression of 24 proteins were detected in the LCMPCS compared to that in the CMS. Among these proteins, fifty were found up-regulated and eleven were found down-regulated. Most of these differently regulated proteins were identified by PMF and database search. These differential expression proteins were reported participating in some key pathway or biology process in cancer cells, indicating that they may present a biomarkers profile and may be helpful for liver-cancer diagnosis.