7
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      ONECUT2 Accelerates Tumor Proliferation Through Activating ROCK1 Expression in Gastric Cancer

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Background

          Transcription factors (TFs) are key regulators which control gene expression during cancer initiation and progression. In the current study, we aimed to explore the proliferative function and clinical significance of TFs in gastric cancer (GC).

          Methods

          Differential analysis was used to investigate the overall expression difference between normal and tumor tissues of each TF in TCGA-STAD cohort. The quantitative real-time polymerase chain reaction (qRT-PCR) was performed to confirm the mRNA expression of one cut homeobox 2 ( ONECUT2) in GC tissues. Western blot analysis was conducted to confirm the protein knockdown efficiency. Cell counting, colony formation, and GC xenograft model assays were performed to confirm the proliferative function of ONECUT2 in GC cells. Gene set enrichment analysis (GESA) and qRT-PCR were conducted to confirm the affected signaling pathways and downstream targets of ONECUT2.

          Results

          Our data indicated that a TF named ONECUT2 was highly expressed in GC and correlated with patients’ poor prognosis. Importantly, knockdown of ONECUT2 dramatically decreased GC cells proliferation, whereas overexpression of ONECUT2 promoted carcinogenesis in GC. Kyoto encyclopedia of genes and genomes (KEGG) analysis revealed that the upregulating ONECUT2 induced the activation of Wnt signaling pathway and cell cycle regulation pathway. We further identified that ONECUT2 boosted gastric cancer cell proliferation through enhancing ROCK1 (Rho associated coiled-coil containing protein kinase 1) mRNA expression. High level of ROCK1 expression rescued proliferative behavior of ONECUT2-deficient GC cells.

          Conclusion

          Our findings demonstrated that ONECUT2 promoted GC cells proliferation through activating ROCK1 expression at the DNA level, suggesting that ONECUT2-ROCK1 axis might be a potential therapeutic target in GC.

          Related collections

          Most cited references17

          • Record: found
          • Abstract: found
          • Article: not found

          Emerging patterns of somatic mutations in cancer.

          Recent advances in technological tools for massively parallel, high-throughput sequencing of DNA have enabled the comprehensive characterization of somatic mutations in a large number of tumour samples. In this Review, we describe recent cancer genomic studies that have assembled emerging views of the landscapes of somatic mutations through deep-sequencing analyses of the coding exomes and whole genomes in various cancer types. We discuss the comparative genomics of different cancers, including mutation rates and spectra, as well as the roles of environmental insults that influence these processes. We highlight the developing statistical approaches that are used to identify significantly mutated genes, and discuss the emerging biological and clinical insights from such analyses, as well as the future challenges of translating these genomic data into clinical impacts.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Targeting Transcription Factors in Cancer.

            Transcription factors (TFs) are commonly deregulated in the pathogenesis of human cancer and are a major class of cancer cell dependencies. Consequently, targeting of TFs can be highly effective in treating particular malignancies, as highlighted by the clinical efficacy of agents that target nuclear hormone receptors. In this review we discuss recent advances in our understanding of TFs as drug targets in oncology, with an emphasis on the emerging chemical approaches to modulate TF function. The remarkable diversity and potency of TFs as drivers of cell transformation justifies a continued pursuit of TFs as therapeutic targets for drug discovery.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: found
              Is Open Access

              ONECUT2 is a driver of neuroendocrine prostate cancer

              Neuroendocrine prostate cancer (NEPC), a lethal form of the disease, is characterized by loss of androgen receptor (AR) signaling during neuroendocrine transdifferentiation, which results in resistance to AR-targeted therapy. Clinically, genomically and epigenetically, NEPC resembles other types of poorly differentiated neuroendocrine tumors (NETs). Through pan-NET analyses, we identified ONECUT2 as a candidate master transcriptional regulator of poorly differentiated NETs. ONECUT2 ectopic expression in prostate adenocarcinoma synergizes with hypoxia to suppress androgen signaling and induce neuroendocrine plasticity. ONEUCT2 drives tumor aggressiveness in NEPC, partially through regulating hypoxia signaling and tumor hypoxia. Specifically, ONECUT2 activates SMAD3, which regulates hypoxia signaling through modulating HIF1α chromatin-binding, leading NEPC to exhibit higher degrees of hypoxia compared to prostate adenocarcinomas. Treatment with hypoxia-activated prodrug TH-302 potently reduces NEPC tumor growth. Collectively, these results highlight the synergy between ONECUT2 and hypoxia in driving NEPC, and emphasize the potential of hypoxia-directed therapy for NEPC patients.
                Bookmark

                Author and article information

                Journal
                Cancer Manag Res
                Cancer Manag Res
                CMAR
                cancmanres
                Cancer Management and Research
                Dove
                1179-1322
                21 July 2020
                2020
                : 12
                : 6113-6121
                Affiliations
                [1 ]Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Fudan University , Shanghai 200032, People’s Republic of China
                Author notes
                Correspondence: Chunyan Du; Jianghong Wu Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Fudan University , 1205 Rm., 3# Bldg., 270 Dong an Road, Shanghai200032, People’s Republic of China Email chunyanfudan@126.com elite53@163.com
                [*]

                These authors contributed equally to this work

                Author information
                http://orcid.org/0000-0002-1386-4612
                http://orcid.org/0000-0002-6923-015X
                Article
                256316
                10.2147/CMAR.S256316
                7398892
                ea4d928a-7c06-4c30-ad57-5a53fa3592ef
                © 2020 Chen et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                : 31 March 2020
                : 30 June 2020
                Page count
                Figures: 4, References: 24, Pages: 9
                Funding
                Funded by: the National Natural Science Foundation of China
                This study was supported by grants from the National Natural Science Foundation of China (81702356).
                Categories
                Original Research

                Oncology & Radiotherapy
                transcriptional factor,onecut2,rock1,gastric cancer,carcinogenesis
                Oncology & Radiotherapy
                transcriptional factor, onecut2, rock1, gastric cancer, carcinogenesis

                Comments

                Comment on this article