The polycomb group (PcG) proteins are epigenetic regulators of gene expression that enhance cell survival. This regulation is achieved via action two multiprotein PcG complexes--PRC2 (EED) and PRC1 [B-cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1)]. These complexes modulate by increasing histone methylation reducing acetylation--leading to a closed chromatin conformation. Activity these associated with increased proliferation We show key in immortalized keratinocytes...

AP1 (jun/fos) transcription factors (c-jun, junB, junD, c-fos, FosB, Fra-1, and Fra-2) are key regulators of epidermal keratinocyte survival differentiation important drivers cancer development. Understanding the role these in epidermis is complicated by fact that each protein expressed, at different levels, multiple cells layers differentiating epidermis, because regulate competing processes (i.e., proliferation, apoptosis, differentiation). Various vivo genetic approaches have been used to...

Intermittent hypoxia (IH) occurs in many pathophysiological conditions. The molecular mechanisms associated with IH, however, have received little attention. Previous studies reported that the c-fos gene via formation of activator protein-1 (AP-1) transcription factor contributes to adaptive responses continuous hypoxia. In present study, using a cell culture model we examined whether IH activates and AP-1 if so, by what mechanisms. Experiments were performed on rat phaeochromocytoma cells...

Treating BRAF inhibitor-resistant melanoma is an important therapeutic goal. Thus, it to identify and target mechanisms of resistance improve therapy. The YAP1 TAZ proteins the Hippo signaling pathway are drivers cancer cell survival, inhibitor resistant factors in melanoma. We examine role YAP1/TAZ stem cells (MCS cells). demonstrate that YAP1, TEAD (TEA domain transcription factor) levels elevated MCS enhance spheroid formation, matrigel invasion tumor formation. Moreover, increased...

Transglutaminase 2 (TG2) expression is required for epidermal squamous cell carcinoma cancer stem survival. However, the molecular signaling mechanisms triggered by TG2 that mediate this survival action are not well understood. Here we show constitutively expressed in ECS cells, where it interacts with α6/β4 integrin to stimulate FAK and Src signaling, leading PI3K activation of phosphoinositide-dependent kinase 1 (PDK1). PDK1 inhibits Hippo enhanced nuclear accumulation YAP1, which...

Abstract Mesothelioma is an aggressive cancer that has a poor prognosis. Tumors develop in the mesothelial lining of pleural and peritoneal cavities response to asbestos exposure. Surgical debulking followed by chemotherapy initially effective, but this treatment ultimately selects for resistant cells form therapy-resistant recurrent tumors. stem (MCS) are highly subpopulation present these tumors responsible tumor maintenance drug resistance. In article, we examine impact targeting...

Epidermal squamous cell carcinoma is among the most common cancers in humans. These tumors are comprised of phenotypically diverse populations cells that display varying potential for proliferation and differentiation. An important goal identifying from this population drive tumor formation. To enrich tumor-forming cells, cancer were grown as spheroids non-attached conditions. We show spheroid-selected form faster growing larger immune-compromised mice compared to non-selected cells....

Polycomb group proteins, including Ezh2, are important candidate stem cell maintenance proteins in epidermal squamous carcinoma. We previously showed that cancer cells (ECS cells) represent a minority of tumors, highly enriched Ezh2 and drive aggressive tumor formation. now show is required for ECS survival, migration, invasion formation this associated with increased histone H3 trimethylation on lysine 27, mark action. also knockdown or treatment inhibitors, GSK126 EPZ-6438, reduces level...

Melanoma is a metastatic cancer associated with poor survival. Here, we study subpopulation of melanoma cells displaying stem cell (MCS cells) properties including elevated expression markers, increased ability to survive as spheroids, and enhanced migration invasion. We show that the Ezh2 survival protein enriched in MCS knockdown or treatment small molecule inhibitors, GSK126 EPZ‐6438, reduces activity. This reduction reduced spheroid formation, migration, Moreover, diet‐derived prevention...

// Matthew L. Fisher 1 , Gautam Adhikary Wen Xu Candace Kerr Jeffrey W. Keillor 5 Richard Eckert 1, 2, 3, 4 Departments of Biochemistry and Molecular Biology, University Maryland School Medicine, Baltimore, Maryland, USA 2 Dermatology, 3 Reproductive Marlene Stewart Greenebaum Cancer, Department Chemistry, Ottawa, Ontario, Canada Correspondence to: Eckert, e-mail: reckert@umaryland.edu Keywords: epidermal squamous cell carcinoma, type II transglutaminase, cancer stem cell, TG2, epithelial...

Human tissue transglutaminase (hTG2) is a multifunctional enzyme. It primarily known for its calcium-dependent transamidation activity that leads to formation of an isopeptide bond between glutamine and lysine residues found on the surface proteins, but it also GTP binding protein. Overexpression unregulated hTG2 have been associated with numerous human diseases, including cancer stem cell survival metastatic phenotype. Herein, we present series targeted covalent inhibitors (TCIs) based our...

PKCδ increases keratinocyte differentiation and suppresses proliferation survival. However, the mechanism of suppression is not well understood. The present studies show that overexpression p21(Cip1) mRNA protein level promoter activity treatment with dominant-negative PKCδ, PKCδ-siRNA, or rottlerin inhibits activation. Analysis upstream regulatory region reveals three DNA segments mediate PKCδ-dependent response element most proximal to transcription start site encodes six GC-rich elements....

Epidermal squamous cell carcinoma is an extremely common type of cancer. Early tumors can be successfully treated by surgery, but recurrent disease aggressive and resistant to therapy. Cisplatin often used as a treatment, the outcome rarely satisfactory. For this reason new strategies are required. Sulforaphane diet‐derived cancer prevention agent that effective in suppressing tumor growth animal models skin We monitored efficacy sulforaphane cisplatin combined therapy for carcinoma. Both...

Abstract Ceramide is recognized as an antiproliferative and proapoptotic sphingolipid metabolite; however, the role of ceramide in inflammation not well understood. To determine C6-ceramide regulating inflammatory responses, human corneal epithelial cells were treated with 80 nm diameter nanoliposome bilayer formulation (Lip-C6) prior to stimulation UV-killed Staphylococcus aureus. Lip-C6 (5 μM) inhibited phosphorylation proinflammatory MAP kinases JNK p38 production neutrophil chemotactic...

Sulforaphane (SFN) is an important cancer preventive agent derived from cruciferous vegetables. We show that SFN treatment suppresses normal human keratinocyte proliferation via a mechanism involves increased expression of p21(Cip1). produces concentration-dependent increase in p21(Cip1) promoter activity stabilization the p53 protein leading to binding response elements. The proximal GC-rich Sp1 factor elements are also required, as SFN-dependent lost when these sites mutated. increases...

Epidermal squamous cell carcinoma (SCC) is among the most common cancers. SCC can be treated by surgical excision, but recurrence of therapy-resistant disease a major problem. We recently showed that YAP1, Hippo signaling transcription adaptor protein, and ∆Np63α, key epidermal stem survival form complex to drive cancer survival. In present study, we demonstrate YAP1 ∆Np63α are important sulforaphane prevention targets. show treatment increases phosphorylation proteolytic degradation. The...

// Gautam Adhikary 1 , Daniel Grun H. Richard Alexander 7 Joseph S. Friedberg 4, 5 Wen Xu Jeffrey W. Keillor 6 Sivaveera Kandasamy and L. Eckert 1, 2, 3, 4 Departments of Biochemistry Molecular Biology, University Maryland School Medicine, Baltimore, Maryland, USA 2 Department Dermatology, 3 Reproductive Greenebaum Comprehensive Cancer Center, Surgery Division General Surgical Oncology, Chemistry, Ottawa, ON, CA Surgery, Rutgers Robert Wood Johnson Medical School, New Brunswick, Jersey,...

Epidermal squamous cell carcinoma (SCC) develops in response to ultraviolet light exposure and is among the most common cancers. The transglutaminase 2 cancer survival protein stimulates activity of YAP1/TEAD transcription complex drive expression genes that promote aggressive epidermal SCC invasion, migration, tumor formation. Therefore, we are interested mechanisms may inhibit these events. Vestigial-like protein-4 (VGLL4) a cofactor/tumor suppressor inhibits several pro-cancer pathways...