Here we report that mice deficient for the proteasome activator, REGg, exhibit a marked resistance to TPA (12-O-tetradecanoyl-phorbol-13-acetate)-induced keratinocyte proliferation, epidermal hyperplasia and onset of papillomas compared with wild-type counterparts. Interestingly, a massive increase of REGg in skin tissues or cells resulting from TPA induces activation of p38 mitogen-activated protein kinase (MAPK/p38). Blocking p38 MAPK activation prevents REGg elevation in HaCaT cells with TPA treatment. AP-1, the downstream effector of MAPK/p38, directly binds to the REGg promoter and activates its transcription in response to TPA stimulation. Furthermore, we find that REGg activates Wnt/b-catenin signalling by degrading GSK-3b in vitro and in cells, increasing levels of CyclinD1 and c-Myc, the downstream targets of b-catenin. Conversely, MAPK/p38 inactivation or REGg deletion prevents the increase of cyclinD1 and c-Myc by TPA. This study demonstrates that REGg acts in skin tumorigenesis mediating MAPK/p38 activation of the Wnt/b-catenin pathway.

Ovarian cancer remains a significant cause of gynecologic cancer mortality, and novel therapeutic strategies are urgently needed in clinic as new treatment options. We previously showed that BET bromodomain inhibitors displayed promising efficacy for the treatment of epithelial ovarian cancer by downregulating pivot transcription factors. However, the potential antitumor activities and molecular mechanisms of other epigenetic or transcriptional therapies have not been systematically determined. Here, by performing an unbiased high-throughput drug screen to identify candidate compounds with antineoplastic effects, we identified THZ1, a recently developed covalent CDK7 inhibitor, as a new transcription-targeting compound that exerted broad cytotoxicity against ovarian tumors. Mechanistically, CDK7 represented a previously unappreciated actionable vulnerability in ovarian cancer, and CDK7 inhibition led to a pronounced dysregulation of gene transcription, with a preferential repression of E2F-regulated genes and transcripts associated with super-enhancers. Our findings revealed the molecular underpinnings of THZ1 potency and established pharmaceutically targeting transcriptional addiction as a promising therapeutic strategy in aggressive ovarian cancer. .

High-grade serous ovarian carcinoma (HGS-OvCa) has the lowest survival rate among all gynecologic cancers and is hallmarked by a high degree of heterogeneity. The Cancer Genome Atlas network has described a gene expression-based molecular classification of HGS-OvCa into Differentiated, Mesenchymal, Immunoreactive and Proliferative subtypes. However, the biological underpinnings and regulatory mechanisms underlying the distinct molecular subtypes are largely unknown. Here we showed that tumor-infiltrating stromal cells significantly contributed to the assignments of Mesenchymal and Immunoreactive clusters. Using reverse engineering and an unbiased interrogation of subtype regulatory networks, we identified the transcriptional modules containing master regulators that drive gene expression of Mesenchymal and Immunoreactive HGS-OvCa. Mesenchymal master regulators were associated with poor prognosis, while Immunoreactive master regulators positively correlated with overall survival. Meta-analysis of 749 HGS-OvCa expression profiles confirmed that master regulators as a prognostic signature were able to predict patient outcome. Our data unraveled master regulatory programs of HGS-OvCa subtypes with prognostic and potentially therapeutic relevance, and suggested that the unique transcriptional and clinical characteristics of ovarian Mesenchymal and Immunoreactive subtypes could be, at least partially, ascribed to tumor microenvironment.

Poriferous TiO2/GO (denoted as TGO-x%) photocatalysts with ultrathin grapheme oxide (GO) layer were prepared by a hydrothermal method, the adsorption and photocatalytic degradation and its kinetics about Methylene blue(MB) were studied systematically. All the TGO-x% showed improved adsorption and photodegradation performance. TGO-25% had excellent adsorptivity while TGO-20% exhibit the highest visible light photocatalytic degradation activity. The adsorption capacity for TGO-25% was 20.25 mg/gcatalyst along with the k1 was about 0.03393 min·gcatalyst/mg, this enhancement was mainly owing to the strong adsorption capacity of GO and the stacking structure of sheets and nanoparticles. GO sheets prevented the agglomeration of TiO2 particles and TiO2 nanoparticles also prevented the agglomeration of GO sheets, which could provides greater surface area. Besides, the remarkably superior photodegradation activity of TiO2/GO composites is mainly attribute to the strong absorption of visible light and the effective charge separation revealed by the photoluminescence, the total removal rate of MB is 97.5% after 35 min adsorption and 140 min degradation, which is 3.5 times higher than that of TiO2.

PAX8 is a prototype lineage-survival oncogene in epithelial ovarian cancer. However, neither its underlying pro-tumorigenic mechanisms nor potential therapeutic implications have been adequately elucidated. Here, we identified an ovarian lineage-specific PAX8 regulon using modified cancer outlier profile analysis, in which PAX8-FGF18 axis was responsible for promoting cell migration in an autocrine fashion. An image-based drug screen pinpointed that PAX8 expression was potently inhibited by small-molecules against histone deacetylases (HDACs). Mechanistically, HDAC blockade altered histone H3K27 acetylation occupancies and perturbed the super-enhancer topology associated with PAX8 gene locus, resulting in epigenetic downregulation of PAX8 transcripts and related targets. HDAC antagonists efficaciously suppressed ovarian tumor growth and spreading as single agents, and exerted synergistic effects in combination with standard chemotherapy. These findings provide mechanistic and therapeutic insights for PAX8-addicted ovarian cancer. More generally, our analytic and experimental approach represents an expandible paradigm for identifying and targeting lineage-survival oncogenes in diverse human malignancies.