Neuronal deletion of Wwox, associated with WOREE syndrome, causes epilepsy and myelin defects.

WWOX-related epileptic encephalopathy (WOREE) syndrome caused by human germline bi-allelic mutations in WWOX is a neurodevelopmental disorder characterized by intractable epilepsy, severe developmental delay, ataxia and premature death at the age of 2-4 years. The underlying mechanisms of WWOX actions are poorly understood. In the current study, we show that specific neuronal deletion of murine Wwox produces phenotypes typical of the Wwox-null mutation leading to brain hyperexcitability, intractable epilepsy, ataxia and postnatal lethality. A significant decrease in transcript levels of genes involved in myelination was observed in mouse cortex and hippocampus. Wwox-mutant mice exhibited reduced maturation of oligodendrocytes, reduced myelinated axons and impaired axonal conductivity. Brain hyperexcitability and hypomyelination were also revealed in human brain organoids with a WWOX deletion. These findings provide cellular and molecular evidence for myelination defects and hyperexcitability in the WOREE syndrome linked to neuronal function of WWOX.

miR-187* Enhances SiHa Cervical Cancer Cell Oncogenicity Via Suppression of WWOX.

BACKGROUND/AIM: Cervical cancer is one of the most common cancers worldwide and a major cause of cancer-related mortality among women. Previous studies have reported that microRNA-miR-187*, which is one of the non-coding parts of the genome producing small conserved ribonucleic acids, is associated with various cancers. In this study, we explored the function of miR-187* in cervical cancer cells. MATERIALS AND METHODS: miR-187* mimic, WWOX reporter constructs, siRNA and overexpression constructs were transfected into SiHa cells to investigate the function and regulatory mechanisms of miR-187*. RESULTS: Exogenous miR-187* was found to increase the oncogenic phenotypes of SiHa cells. The tumor suppressor gene WWOX is a novel target of miR-187* in SiHa cells. WWOX siRNA suppressed endogenous WWOX expression and increased the oncogenic phenotypes of SiHa cells. Exogenous WWOX expression was able to suppress the oncogenic phenotypes of SiHa cells and rescue cells from miR-187*-induced migration. CONCLUSION: miR-187* seems to enhance SiHa cervical cancer cell oncogenicity via suppression of the WWOX pathway.

A p53/TIAF1/WWOX triad exerts cancer suppression but may cause brain protein aggregation due to p53/WWOX functional antagonism.

BACKGROUND: Tumor suppressor WWOX physically binds p53 and TIAF1 and together induces apoptosis and tumor suppression. To understand the molecular action, here we investigated the formation of WWOX/TIAF1/p53 triad and its regulation of cancer cell migration, anchorage-independent growth, SMAD promoter activation, apoptosis, and potential role in neurodegeneration. METHODS: Time-lapse microscopy was used to measure the extent of cell migration. Protein/protein interactions were determined by co-immunoprecipitation, FRET microscopy, and yeast two-hybrid analysis. The WWOX/TIAF1/p53 triad-mediated cancer suppression was determined by measuring the extent of cell migration, anchorage-independent growth, SMAD promoter activation, and apoptosis. p53-deficient lung cancer cell growth in nude mice was carried out to assess the tumor suppressor function of ectopic p53 and/or WWOX. RESULTS: Wwox-deficient MEF cells exhibited constitutive Smad3 and p38 activation and migrated individually and much faster than wild type cells. TGF-ß increased the migration of wild type MEF cells, but significantly suppressed Wwox knockout cell migration. While each of the triad proteins is responsive to TGF-ß stimulation, ectopically expressed triad proteins suppressed cancer cell migration, anchorage-independent growth, and SMAD promoter activation, as well as caused apoptosis. The effects are due in part to TIAF1 polymerization and its retention of p53 and WWOX in the cytoplasm. p53 and TIAF1 were effective in suppressing anchorage-independent growth, and WWOX ineffective. p53 and TIAF1 blocked WWOX or Smad4-regulated SMAD promoter activation. WWOX suppressed lung cancer NCI-H1299 growth and inhibited splenomegaly by inflammatory immune response, and p53 blocked the event in nude mice. The p53/WWOX-cancer mice exhibited BACE upregulation, APP degradation, tau tangle formation, and amyloid ß generation in the brain and lung. CONCLUSION: The WWOX/TIAF1/p53 triad is potent in cancer suppression by blocking cancer cell migration, anchorage-independent growth and SMAD promoter activation, and causing apoptosis. Yet, p53 may functionally antagonize with WWOX. p53 blocks WWOX inhibition of inflammatory immune response induced by cancer, and this leads to protein aggregation in the brain as seen in the Alzheimer's disease and other neurodegeneration.