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      Chromodomain Helicase DNA-Binding Protein 5 Inhibits Renal Cell Carcinoma Tumorigenesis by Activation of the p53 and RB Pathways

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          Abstract

          Chromodomain helicase DNA-binding protein 5 (CHD5) plays a crucial tumor suppressor role in multiple types of tumors. For this study, we investigated its clinical significance and the molecular mechanism(s) underlying tumorigenesis in renal cell carcinoma (RCC). Initially, CHD5 expression was assessed in primary tumor tissue and in tissue array. Correlations among CHD5 expression and clinicopathological characteristics were analyzed. Next, lentivirus-mediated CHD5 overexpression in the ACHN and 769-P cells was used to assess effects on proliferation, migration, invasion ability, and the regulation of the p14 ARF/p53 and p16 INK4a/RB signaling pathways. Finally, a xenograft mouse model was used to verify its impact on tumor growth in vivo. Results demonstrated that CHD5 was downregulated in tumor tissues and that low CHD5 expression was correlated with advanced TNM stage, high Fuhrman grade, lymph node metastasis, and poor survival. Overexpression of CHD5 inhibited proliferation, migration, and invasion in vitro; prompted cell cycle G1 phase arrest; induced apoptosis; and suppressed tumor growth in vivo. Furthermore, we confirmed that CHD5 activates the p53 and RB pathways to inhibit tumorigenesis in RCC. In summary, CHD5 is involved in the initiation and progression of RCC and may serve as a diagnostic biomarker and a potential therapeutic target for RCC.

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          Most cited references 34

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          Genome-scale transcriptional activation by an engineered CRISPR-Cas9 complex.

          Systematic interrogation of gene function requires the ability to perturb gene expression in a robust and generalizable manner. Here we describe structure-guided engineering of a CRISPR-Cas9 complex to mediate efficient transcriptional activation at endogenous genomic loci. We used these engineered Cas9 activation complexes to investigate single-guide RNA (sgRNA) targeting rules for effective transcriptional activation, to demonstrate multiplexed activation of ten genes simultaneously, and to upregulate long intergenic non-coding RNA (lincRNA) transcripts. We also synthesized a library consisting of 70,290 guides targeting all human RefSeq coding isoforms to screen for genes that, upon activation, confer resistance to a BRAF inhibitor. The top hits included genes previously shown to be able to confer resistance, and novel candidates were validated using individual sgRNA and complementary DNA overexpression. A gene expression signature based on the top screening hits correlated with markers of BRAF inhibitor resistance in cell lines and patient-derived samples. These results collectively demonstrate the potential of Cas9-based activators as a powerful genetic perturbation technology.
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            Cell-Cycle Therapeutics Come of Age.

             Matthew Ingham,  Gary K. Schwartz (corresponding) (2017)
            The ability to sustain unscheduled proliferation is a hallmark of cancer. The normal process of cell division occurs via the cell cycle, a series of highly regulated steps that are orchestrated at the molecular level by specific cyclins that act in association with cyclin-dependent kinases (CDKs). Cyclin D and CDK4/6 play a key role in cell-cycle progression by phosphorylating and inactivating the retinoblastoma protein, a tumor suppressor that restrains G1- to S-phase progression. The first-generation CDK inhibitors demonstrated broad activity upon several CDKs, which likely explains their considerable toxicities and limited efficacy. Palbociclib, ribociclib, and abemaciclib represent a new class of highly specific ATP-competitive CDK4/6 inhibitors that induce reversible G1-phase cell-cycle arrest in retinoblastoma-positive tumor models. Both palbociclib and ribociclib have been approved in combination with hormone-based therapy for the treatment of naïve hormone receptor-positive advanced breast cancer on the basis of an improvement in progression-free survival. In general, CDK4/6 inhibitors are cytostatic as monotherapy but demonstrate favorable tolerability, which has prompted interest in combination approaches. Combinations with phosphatidylinositol 3-kinase and mammalian target of rapamycin inhibitors in breast cancer, and inhibitors of the RAS/RAF/mitogen-activated protein kinase pathway in RAS-mutant cancers are particularly promising approaches that are currently being evaluated. Although the subject of intense preclinical study, predictive biomarkers for response and resistance to these drugs remain largely undefined. CDK4/6 inhibitors have emerged as the most promising of the cell-cycle therapeutics and intense efforts are now underway to expand the reach of this paradigm.
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              The INK4a/ARF network in tumour suppression.

               C Sherr (2001)
              The retinoblastoma protein (RB) and p53 transcription factor are regulated by two distinct proteins that are encoded by the INK4a/ARF locus. Genes encoding these four tumour suppressors are disabled, either in whole or in part, in most human cancers. A complex signalling network that interconnects the activities of RB and p53 monitors oncogenic stimuli to provide a cell-autonomous mode of tumour surveillance.
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                Author and article information

                Contributors
                Journal
                Biomed Res Int
                Biomed Res Int
                BMRI
                BioMed Research International
                Hindawi
                2314-6133
                2314-6141
                2020
                28 September 2020
                : 2020
                Affiliations
                1Department of Urology, ZhuJiang Hospital of Southern Medical University, Guangzhou 510282, China
                2Guangdong Provincial Key Laboratory of Geriatric Infection and Organ Function Support, Department of Medical Intensive Care Unit, General Hospital of Southern Theatre Command, Guangzhou 510010, China
                3Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
                Author notes

                Academic Editor: Guiming Liu

                Article
                10.1155/2020/5425612
                7542531
                Copyright © 2020 Sheng Huang et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Funding
                Funded by: Natural Science Foundation of Guangdong Province
                Award ID: 2017A030310100
                Funded by: Guangzhou Science and Technology Program key projects
                Award ID: 201610010174
                Award ID: 20170701006
                Funded by: National Natural Science Foundation of China
                Award ID: 81771710
                Categories
                Research Article

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