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Andrea Milelli, Chiara Marchetti, Eleonora Turrini, Elena Catanzaro, Roberta Mazzone, Daniela Tomaselli, Carmela Fimognari, Vincenzo Tumiatti, Anna Minarini
Epigenetic modulators Histone deacetylases (HDACs) and Lysine demethylase (LSD1) are validated targets for anticancer therapy. Both HDAC1/2 and LSD1 are found in association with the repressor protein CoREST in a transcriptional co-repressor complex, which is responsible for gene silencing. Combined modulation of both targets results in a synergistic antiproliferative activity. In the present investigation, we report about the design and synthesis of a series of polyamine-based HDACs-LSD1 dual binding inhibitors obtained by coupling Vorinostat and Tranylcypromine...
February 17, 2018: Bioorganic & Medicinal Chemistry Letters
Ye He, Hai-Bo Li, Xin Li, Yi Zhou, Xiao-Bo Xia, Wei-Tao Song
BACKGROUND/AIMS: Retinal Müller cells could be induced to differentiate into retinal ganglion cells (RGCs), but RGCs derived from Müller cells have defects in axon growth, leading to a defect in signal conduction. In this study we aimed to explore the role of miR-124 in axon growth of RGCs derived from Müller cells. METHODS: Müller cells were isolated from rat retina and induced to dedifferentiate into retinal stem cells. The stem cells were infected by PGC-FU-Atoh7-GFP lentivirus and then transfected with miR-124 or anti-miR-124, and the length of axon was compared...
February 5, 2018: Cellular Physiology and Biochemistry
Jian-Yue Wang, Yong Feng, Yan-Hong Fu, Guang-Li Liu
Postoperative cognitive dysfunction in elderly patients has been related to neurodegenerative disorders and mortality. Sevoflurane anesthesia has been implicated in both postoperative cognitive dysfunction and neurotoxicity. Given the advantages of using inhaled anesthetics like sevoflurane, it is important to understand how their usage results in neurotoxicity and subsequently devise ways to circumvent or attenuate the anesthetic-mediated induction in neurotoxicity. Long noncoding RNAs (LncRNAs) are a group of > 200 bp long RNAs and show specific spatiotemporal expression profiles...
January 19, 2018: Journal of Molecular Neuroscience: MN
Jay H Kalin, Muzhou Wu, Andrea V Gomez, Yun Song, Jayanta Das, Dawn Hayward, Nkosi Adejola, Mingxuan Wu, Izabela Panova, Hye Jin Chung, Edward Kim, Holly J Roberts, Justin M Roberts, Polina Prusevich, Jeliazko R Jeliazkov, Shourya S Roy Burman, Louise Fairall, Charles Milano, Abdulkerim Eroglu, Charlotte M Proby, Albena T Dinkova-Kostova, Wayne W Hancock, Jeffrey J Gray, James E Bradner, Sergio Valente, Antonello Mai, Nicole M Anders, Michelle A Rudek, Yong Hu, Byungwoo Ryu, John W R Schwabe, Andrea Mattevi, Rhoda M Alani, Philip A Cole
Here we report corin, a synthetic hybrid agent derived from the class I HDAC inhibitor (entinostat) and an LSD1 inhibitor (tranylcypromine analog). Enzymologic analysis reveals that corin potently targets the CoREST complex and shows more sustained inhibition of CoREST complex HDAC activity compared with entinostat. Cell-based experiments demonstrate that corin exhibits a superior anti-proliferative profile against several melanoma lines and cutaneous squamous cell carcinoma lines compared to its parent monofunctional inhibitors but is less toxic to melanocytes and keratinocytes...
January 4, 2018: Nature Communications
Waleed A Zalloum, Hiba M Zalloum
Epigenetic targeting of cancer is a recent effort to manipulate the gene without destroying the genetic material. Lysine-specific demethylase 1 (LSD1) is one of the enzymes associated with the chromatin for post-translational modifications, where it demethylates lysine amino acid in the chromatin H3 tail. Many studies showed that inhibiting LSD1 could potentially be used to treat cancer epigenetically. LSD1 is associated with its corepressor protein CoREST, and it uses tetrahydrofolate as a co-factor to accept CH2 from the demethylation process...
December 26, 2017: Journal of Chemical Information and Modeling
Lifang Li, Xinhua Liu, Lin He, Jianguo Yang, Fei Pei, Wanjin Li, Shumeng Liu, Zhe Chen, Guojia Xie, Bosen Xu, Xia Ting, Zihan Zhang, Tong Jin, Xujun Liu, Wenting Zhang, Shuai Yuan, Ziran Yang, Chongyang Wu, Yu Zhang, Xiaohan Yang, Xia Yi, Jing Liang, Yongfeng Shang, Luyang Sun
EGFR is required for animal development, and dysregulation of EGFR is critically implicated in malignant transformation. However, the molecular mechanism underlying the regulation of EGFR expression remains poorly explored. Here we report that the zinc-finger protein ZNF516 is a transcription repressor. ZNF516 is physically associated with the CtBP/LSD1/CoREST complex and transcriptionally represses a cohort of genes including EGFR that are critically involved in cell proliferation and motility. We demonstrate that the ZNF516-CtBP/LSD1/CoREST complex inhibits the proliferation and invasion of breast cancer cells in vitro and suppresses breast cancer growth and metastasis in vivo...
September 25, 2017: Nature Communications
Tabish Hussain, Dhurjhoti Saha, Gunjan Purohit, Anirban Kar, Anand Kishore Mukherjee, Shalu Sharma, Suman Sengupta, Parashar Dhapola, Basudeb Maji, Sreekanth Vedagopuram, Nobuko T Horikoshi, Nobuo Horikoshi, Raj K Pandita, Santanu Bhattacharya, Avinash Bajaj, Jean-François Riou, Tej K Pandita, Shantanu Chowdhury
We observed extra-telomeric binding of the telomere repeat binding factor TRF2 within the promoter of the cyclin-dependent kinase CDKNIA (p21/CIP1/WAF1). This result in TRF2 induced transcription repression of p21. Interestingly, p21 repression was through engagement of the REST-coREST-LSD1-repressor complex and altered histone marks at the p21 promoter in a TRF2-dependent fashion. Furthermore, mutational analysis shows p21 repression requires interaction of TRF2 with a p21 promoter G-quadruplex. Physiologically, TRF2-mediated p21 repression attenuated drug-induced activation of cellular DNA damage response by evading G2/M arrest in cancer cells...
September 14, 2017: Scientific Reports
I J de Castro, H A Amin, V Vinciotti, P Vagnarelli
Tight regulation of gene expression is achieved by a variety of protein complexes that selectively bind chromatin, modify it and change its transcription competency. Histone acetylases (HATs) and deacetylases (HDACs) play an important role in this process. They can generate transcriptionally active or inactive chromatin through the addition (HATs) or removal (HDACs) of acetyl groups on histones, respectively. Repo-Man is a Protein Phosphatase 1 targeting subunit that accumulates on chromosomes during mitotic exit and mediates the removal of mitotic histone H3 phosphorylations...
September 14, 2017: Cell Cycle
Abhinav Dhall, Caroline E Weller, Aurea Chu, Patrick M M Shelton, Champak Chatterjee
Lysine-specific demethylase 1 (LSD1) downregulates eukaryotic gene activity by demethylating mono- and dimethylated Lys4 in histone H3. Elucidating the biochemical crosstalk of LSD1 with histone post-translational modifications (PTMs) is essential for developing LSD1-targeted therapeutics in human cancers. We interrogated the small ubiquitin-like modifier (SUMO)-driven regulation of LSD1 activity with semisynthetic nucleosomes containing site-specifically methylated and sumoylated histones. We discovered that nucleosomes containing sumoylated histone H4 (suH4), a modification associated with gene repression, stimulate LSD1 activity by a mechanism dependent upon the SUMO-interaction motif in CoREST...
September 15, 2017: ACS Chemical Biology
Jing Li, Jing Wang, Yan Zhong, Ruixia Guo, Danxia Chu, Haifeng Qiu, Zhongfu Yuan
Long non-coding RNAs (lncRNAs) play critical roles in the initiation and progression of human cancers. HOX transcript antisense RNA (HOTAIR) is an lncRNA localized to the mammalian HOXC gene cluster; it can interact with polycomb repressive complex 2 and the lysine-specific histone demethylase/CoREST/REST complex, and it manipulates the expression of various genes. HOTAIR promotes tumor invasion and metastasis by silencing tumor suppressors, and activating oncogenes and signaling pathways. HOTAIR is deregulated in many human cancers; despite its critical roles in health and disease, the underlying mechanisms governing HOTAIR function are unknown...
2017: Cancer Cell International
Julie H Coleman, Brian Lin, James E Schwob
Neurons in the olfactory epithelium (OE) each express a single dominant olfactory receptor (OR) allele from among roughly 1,000 different OR genes. While monogenic and monoallelic OR expression has been appreciated for over two decades, regulators of this process are still being described; most recently, epigenetic modifiers have been of high interest as silent OR genes are decorated with transcriptionally repressive trimethylated histone 3 lysine 9 (H3K9me3) whereas active OR genes are decorated with transcriptionally activating trimethylated histone 3 lysine 4 (H3K4me3)...
June 9, 2017: Journal of Comparative Neurology
Yuichi Amano, Masaki Kikuchi, Shin Sato, Shigeyuki Yokoyama, Takashi Umehara, Naoki Umezawa, Tsunehiko Higuchi
Lysine-specific demethylase 1 (LSD1/KDM1A) is a flavoenzyme demethylase, which removes mono- and dimethyl groups from histone H3 Lys4 (H3K4) or Lys9 (H3K9) in complexes with several nuclear proteins. Since LSD1 is implicated in the tumorigenesis and progression of various cancers, LSD1-specific inhibitors are considered as potential anti-cancer agents. A modified H3 peptide with substitution of Lys4 to Met [H3K4M] is already known to be a potent competitive inhibitor of LSD1. In this study, we synthesized a series of H3K4M peptide derivatives and evaluated their LSD1-inhibitory activities in vitro...
May 1, 2017: Bioorganic & Medicinal Chemistry
Paola Vianello, Luca Sartori, Federica Amigoni, Anna Cappa, Giovanni Fagá, Raimondo Fattori, Elena Legnaghi, Giuseppe Ciossani, Andrea Mattevi, Giuseppe Meroni, Loris Moretti, Valentina Cecatiello, Sebastiano Pasqualato, Alessia Romussi, Florian Thaler, Paolo Trifiró, Manuela Villa, Oronza A Botrugno, Paola Dessanti, Saverio Minucci, Stefania Vultaggio, Elisa Zagarrí, Mario Varasi, Ciro Mercurio
The balance of methylation levels at histone H3 lysine 4 (H3K4) is regulated by KDM1A (LSD1). KDM1A is overexpressed in several tumor types, thus representing an emerging target for the development of novel cancer therapeutics. We have previously described ( Part 1, DOI 10.1021.acs.jmedchem.6b01018 ) the identification of thieno[3,2-b]pyrrole-5-carboxamides as novel reversible inhibitors of KDM1A, whose preliminary exploration resulted in compound 2 with biochemical IC50 = 160 nM. We now report the structure-guided optimization of this chemical series based on multiple ligand/KDM1A-CoRest cocrystal structures, which led to several extremely potent inhibitors...
March 9, 2017: Journal of Medicinal Chemistry
Luca Sartori, Ciro Mercurio, Federica Amigoni, Anna Cappa, Giovanni Fagá, Raimondo Fattori, Elena Legnaghi, Giuseppe Ciossani, Andrea Mattevi, Giuseppe Meroni, Loris Moretti, Valentina Cecatiello, Sebastiano Pasqualato, Alessia Romussi, Florian Thaler, Paolo Trifiró, Manuela Villa, Stefania Vultaggio, Oronza A Botrugno, Paola Dessanti, Saverio Minucci, Elisa Zagarrí, Daniele Carettoni, Lucia Iuzzolino, Mario Varasi, Paola Vianello
Lysine specific demethylase 1 KDM1A (LSD1) regulates histone methylation and it is increasingly recognized as a potential therapeutic target in oncology. We report on a high-throughput screening campaign performed on KDM1A/CoREST, using a time-resolved fluorescence resonance energy transfer (TR-FRET) technology, to identify reversible inhibitors. The screening led to 115 hits for which we determined biochemical IC50, thus identifying four chemical series. After data analysis, we have prioritized the chemical series of N-phenyl-4H-thieno[3, 2-b]pyrrole-5-carboxamide for which we obtained X-ray structures of the most potent hit (compound 19, IC50 = 2...
March 9, 2017: Journal of Medicinal Chemistry
Yue Jin, Bo Huo, Xueqi Fu, Tian Hao, Yu Zhang, Yidi Guo, Xin Hu
Histone methylation is a complicate and dynamic epigenetic modification that regulates gene transcription, chromosomal structure and cell differentiation. Here, we discovered the interaction between the H3K4 demethylase, lysine specific demethylase 1 (LSD1, an important component of CoREST repressor complex) and the H3K27 methyltransferase, enhancer of zeste homolog 2 (EZH2, an essential component of PRC2). Immuno-precipitation and GST-pull down assay were performed to observe the interaction between the proteins...
April 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
K Saud, J Cánovas, C I Lopez, F A Berndt, E López, J C Maass, A Barriga, M Kukuljan
The development of the cerebral cortex requires the coordination of multiple processes ranging from the proliferation of progenitors to the migration and establishment of connectivity of the newborn neurons. Epigenetic regulation carried out by the COREST/LSD1 complex has been identified as a mechanism that regulates the development of pyramidal neurons of the cerebral cortex. We now identify the association of the multifunctional RNA-binding protein SFPQ to LSD1 during the development of the cerebral cortex...
April 2017: International Journal of Developmental Neuroscience
Lin Shan, Xing Zhou, Xinhua Liu, Yue Wang, Dongxue Su, Yongqiang Hou, Na Yu, Chao Yang, Beibei Liu, Jie Gao, Yang Duan, Jianguo Yang, Wanjin Li, Jing Liang, Luyang Sun, Kexin Chen, Chenghao Xuan, Lei Shi, Yan Wang, Yongfeng Shang
Although clinically associated with severe developmental defects, the biological function of FOXK2 remains poorly explored. Here we report that FOXK2 interacts with transcription corepressor complexes NCoR/SMRT, SIN3A, NuRD, and REST/CoREST to repress a cohort of genes including HIF1β and EZH2 and to regulate several signaling pathways including the hypoxic response. We show that FOXK2 inhibits the proliferation and invasion of breast cancer cells and suppresses the growth and metastasis of breast cancer. Interestingly, FOXK2 is transactivated by ERα and transrepressed via reciprocal successive feedback by HIF1β/EZH2...
November 14, 2016: Cancer Cell
Delphine Duteil, Milica Tosic, Franziska Lausecker, Hatice Z Nenseth, Judith M Müller, Sylvia Urban, Dominica Willmann, Kerstin Petroll, Nadia Messaddeq, Laura Arrigoni, Thomas Manke, Jan-Wilhelm Kornfeld, Jens C Brüning, Vyacheslav Zagoriy, Michael Meret, Jörn Dengjel, Toufike Kanouni, Roland Schüle
Previous work indicated that lysine-specific demethylase 1 (Lsd1) can positively regulate the oxidative and thermogenic capacities of white and beige adipocytes. Here we investigate the role of Lsd1 in brown adipose tissue (BAT) and find that BAT-selective Lsd1 ablation induces a shift from oxidative to glycolytic metabolism. This shift is associated with downregulation of BAT-specific and upregulation of white adipose tissue (WAT)-selective gene expression. This results in the accumulation of di- and triacylglycerides and culminates in a profound whitening of BAT in aged Lsd1-deficient mice...
October 18, 2016: Cell Reports
Christina R Tyler, Matthew T Labrecque, Elizabeth R Solomon, Xun Guo, Andrea M Allan
Exposure to arsenic, a common environmental toxin found in drinking water, leads to a host of neurological pathologies. We have previously demonstrated that developmental exposure to a low level of arsenic (50ppb) alters epigenetic processes that underlie deficits in adult hippocampal neurogenesis leading to aberrant behavior. It is unclear if arsenic impacts the programming and regulation of embryonic neurogenesis during development when exposure occurs. The master negative regulator of neural-lineage, REST/NRSF, controls the precise timing of fate specification and differentiation of neural stem cells (NSCs)...
January 2017: Neurotoxicology and Teratology
A Silvina Nacht, Miguel Beato, Guillermo P Vicent
How genes are repressed by steroid hormones remains a matter of debate, and several indirect mechanisms have been proposed. We found that the ligand-activated progesterone receptor recruits to the promoter of downregulated genes a repressor complex composed of HP1γ, the lysine demethylase LSD1, histone deacetylases, coREST, the RNA SRA, and the ATPase BRG1. BRG1 is needed for chromatin remodeling and facilitates the deposition of linker histone variant H1.2, which compacts chromatin and hinders RNA polymerase loading and transcription...
January 2017: Transcription
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