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Active DNA-dependent ATPase A Domain inhibitor (ADAADi) is the only known inhibitor of ATP-dependent chromatin remodeling proteins that targets the ATPase domain of these proteins. The molecule is synthesized by aminoglycoside phosphotransferase enzyme in the presence of aminoglycosides. ADAADi interacts with ATP-dependent chromatin remodeling proteins through motif Ia present in the conserved helicase domain, and thus, can potentially inhibit all members of this family of proteins. We show that mammalian cells are sensitive to ADAADi but with variable responses in different cell lines. ADAADi can be generated from a wide variety of aminoglycosides; however, cells showed differential response to ADAADi generated from various aminoglycosides. Using HeLa and DU145 cells as model system we have explored the effect of ADAADi on cellular functions. We show that the transcriptional network of a cell type is altered when treated with sub-lethal concentration of ADAADi. Although ADAADi has no known effects on DNA chemical and structural integrity, expression of DNA-damage response genes was altered. The transcripts encoding for the pro-apoptotic proteins were found to be upregulated while the anti-apoptotic genes were found to be downregulated. This was accompanied by increased apoptosis leading us to hypothesize that the ADAADi treatment promotes apoptotic-type of cell death by upregulating the transcription of pro-apoptotic genes. ADAADi also inhibited migration of cells as well as their colony forming ability leading us to conclude that the compound has effective anti-tumor properties.

// Qiong Wu 1 , Pasil Madany 1 , Jason R. Dobson 1 , Jake M. Schnabl 1 , Soni Sharma 2 , Tara C. Smith 1 Andre J. van Wijnen 3 , Janet L. Stein 4 , Jane B. Lian 4 , Gary S. Stein 4 , Rohini Muthuswami 2 , Anthony N. Imbalzano 1 , Jeffrey A. Nickerson 1 1 Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA, USA 2 School of Life Sciences, Jawaharlal Nehru University, New Delhi, Delhi, India 3 Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA 4 Department of Biochemistry and Vermont Cancer Center for Basic and Translational Research, University of Vermont College of Medicine, Burlington, WA, USA Correspondence to: Anthony N. Imbalzano, email: anthony.imbalzano@umassmed.edu Jeffrey A. Nickerson, email: jeffrey.nickerson@umassmed.edu Keywords: breast cancer, metabolism, lipogenesis, gene regulation, BRG1 Received: January 07, 2016 Accepted: May 01, 2016 Published: May 20, 2016 ABSTRACT Cancer cells reprogram cellular metabolism to meet the demands of growth. Identification of the regulatory machinery that regulates cancer-specific metabolic changes may open new avenues for anti-cancer therapeutics. The epigenetic regulator BRG1 is a catalytic ATPase for some mammalian SWI/SNF chromatin remodeling enzymes. BRG1 is a well-characterized tumor suppressor in some human cancers, but is frequently overexpressed without mutation in other cancers, including breast cancer. Here we demonstrate that BRG1 upregulates de novo lipogenesis and that this is crucial for cancer cell proliferation. Knockdown of BRG1 attenuates lipid synthesis by impairing the transcription of enzymes catalyzing fatty acid and lipid synthesis. Remarkably, exogenous addition of palmitate, the key intermediate in fatty acid synthesis, rescued the cancer cell proliferation defect caused by BRG1 knockdown. Our work suggests that targeting BRG1 to reduce lipid metabolism and, thereby, to reduce proliferation, has promise for epigenetic therapy in triple negative breast cancer.

Brahma related gene product 1 (BRG1) is an ATPase that drives the catalytic activity of a subset of the mammalian SWI/SNF chromatin remodeling enzymes. BRG1 is overexpressed in most human breast cancer tumors without evidence of mutation and is required for breast cancer cell proliferation. We demonstrate that knockdown of BRG1 sensitized triple negative breast cancer cells to chemotherapeutic drugs used to treat breast cancer. An inhibitor of the BRG1 bromodomain had no effect on breast cancer cell viability, but an inhibitory molecule that targets the BRG1 ATPase activity recapitulated the increased drug efficacy observed in the presence of BRG1 knockdown. We further demonstrate that inhibition of BRG1 ATPase activity blocks the induction of ABC transporter genes by these chemotherapeutic drugs and that BRG1 binds to ABC transporter gene promoters. This inhibition increased intracellular concentrations of the drugs, providing a likely mechanism for the increased chemosensitivity. Since ABC transporters and their induction by chemotherapy drugs are a major cause of chemoresistance and treatment failure, these results support the idea that targeting the enzymatic activity of BRG1 would be an effective adjuvant therapy for breast cancer.

This report represents the first study of keratinophilic fungi present in soils of Jamaica. Out of the 40 soil samples examined from different habitats, 30 (75%) were positive for the presence of keratinophilic fungi, yielding 36 isolates of keratinophilic fungi. Microsporum gypseum complex (represented by 16 isolates of M. gypseum, and four of M. fulvum) was most frequent, being present in 50% of the samples. A very high occurrence of this dermatophyte in Jamaican soil is of public health significance. The remaining isolates of keratinophilic fungi were represented by Chrysosporium spp (mainly C. indicum and C. tropicum) and Sepedonium sp. Esta comunicação representa o primeiro estudo sobre fungos queratinofílicos presentes em solos da Jamaica. De 40 amostras de solo examinadas de diferentes localidades, 30 (75%) foram positivas para a presença de fungos queratinofílicos permitindo 36 isolamentos dos mesmos. O complexo Microsporum gypseum (representados por 16 isolamentos de M. gypseum e quatro de M. fulvum) foi o mais frequente, estando presente em 50% das amostras. A muito alta ocorrência deste dermatófito no solo da Jamaica é significante para a saúde pública. Os isolados remanescentes de fungos queratinofílicos foram representados pelo Chrysosporium spp (principalmente C. indicum e C. tropicum) e Sepedonium sp.

Introduction: Information on the prevalence of keratinophilic fungi in West Indies is scanty. Occurrence of keratinophilic fungi in soils of St. Kitts and Nevis has not been investigated previously. Methodology: The prevalence of keratinophilic fungi was investigated in 108 samples of soils of varying habitats from St. Kitts and 55 such samples from Nevis by hair-baiting technique. Fungal growths appearing on the hair baits after four to eight weeks of incubation at room temperature were microscopically examined and cultured on mycological media. Cultures were identified on the basis of colonial and microscopic features. Results: Forty-nine (45%) of the samples from St. Kitts and 38 (69%) from Nevis were positive for keratinophilic fungi. Microsporum gypseum complex, a well-known geophilic dermatophyte, was the most frequently recovered species being present in 15.7% of soils of St. Kitts and 40% of soils of Nevis. The next commonest species recovered was Chrysosporium indicum , represented by 15 (13.9%) isolates from St. Kitts and seven (12.7%) isolates from Nevis. Other infrequently isolated keratinophilic species included Chrysosporium tropicum , Chrysosporium keratinophilum , and unidentified Chrysosporium species. Conclusions: This study is the first of its kind in the islands of St. Kitts and Nevis. A high incidence of M. gypseum complex in the soil of these islands is a noteworthy finding of public health significance.