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  • br In summary our findings

    2019-10-21


    In summary, our findings indicate that the novel synthetic com-pound SM934-Testosterone can suppress the viability, proliferation and metastasis of MDA-MB-231 and SK-BR-3 EPZ-6438 via inhibiting the ex-pression of Cathepsin K. Furthermore, the suppression of Cathepsin K can lead to the knockdown of Bcl-xL, which is widely considered to be closely related to the apoptosis and metastasis of cancer cells. Moreover, the study of SM934-Testosterone's effects in vivo convinced that the structure of SM934-Testosterone still needs further optimized, and we will explore it in our future study. Overall, this research studies the effects of the promising new compound SM934-Testosterone on  European Journal of Pharmacology 858 (2019) 172382
    breast cancer cells and provides insights into the mechanisms.
    4.1. CRediT authorship contribution statement
    Xiangyu Gu: Investigation, Methodology, Data curation, Writing-original draft, Writing - review & editing. Yayuan Peng: Computational target prediction and pathway enrichment analysis, writing – draft & review. Yuyu Zhao: Data Curation. Xin Liang: Writing - review & editing. Yun Tang: Conceptualization, Writing – review & editing, Supervision, Software, Resources. Jianwen Liu: Writing - review & editing, Supervision, Conceptualization and Resources.
    Conflicts of interest
    The authors have no potential conflict of financial or intellectual interests.
    Acknowledgments
    The authors thank Professor Bubing Zeng for providing the samples of the synthetic compounds. This work was supported by the National Natural Science Foundation of China [Grant 81673356].
    Appendix A. Supplementary data
    References
    Fono viä‡,, M., Turk, B., 2014. Cysteine cathepsins and extracellular matrix degradation.
    Galal, A.M., Gul, W., Slade, D., Ross, S.A., Feng, S., Hollingshead, M.G., Alley, M.C., Kaur, G., Elsohly, M.A., 2009. Synthesis and evaluation of dihydroartemisinin and dihy-droartemisitene acetal dimers showing anticancer and antiprotozoal activity. Bioorg.
    Lai, H., Singh, N.P., 1995. Selective cancer cell cytotoxicity from exposure to dihy-droartemisinin and holotransferrin. Cancer Lett. 91 (1), 41.
    Le, T.D., 2012. Therapeutic inhibition of cathepsin K—reducing bone resorption while maintaining bone formation. BoneKEy Rep. 1 (5), 67.
    Contents lists available at ScienceDirect
    Cancer Letters
    journal homepage: www.elsevier.com/locate/canlet
    Original Articles
    A novel DNA-binding motif in prostate tumor overexpressed-1 (PTOV1) T
    required for the expression of ALDH1A1 and CCNG2 in cancer cells
    Valentina Maggioa,1, Verónica Cánovasa,1, Alex J. Félixb, Valentí Gómeza, Inés de Torresc, María Eugenia Semideyc, Juan Morotea,d, Verónique Noéb, Carlos J. Ciudadb, Rosanna Paciuccia,∗ a Biochemistry Service, Vall d’Hebron University Hospital and Universitat Autònoma de Barcelona, Pg. Vall d’Hebron 119-129, Barcelona, 08035, Spain
    b Department of Biochemistry and Physiology, School of Pharmacy, And Institute of Nanoscience and Nanotechnology, University of Barcelona, Avinguda Joan XXIII 27, 08028, Barcelona, Spain
    c Department of Pathology, Vall d’Hebron University Hospital, Barcelona, Spain
    d Deparment of Urology, Vall d’Hebron University Hospital, and Universitat Autònoma de Barcelona, Spain
    Keywords:
    PTOV1
    DNA-Binding motif
    AT-Hook
    Aggressive prostate cancer Chromatin immunoprecipitation EMSA 
    PTOV1 is a transcription and translation regulator and a promoter of cancer progression. Its overexpression in prostate cancer induces transcription of drug resistance and self-renewal genes, and docetaxel resistance. Here we studied PTOV1 ability to directly activate the transcription of ALDH1A1 and CCNG2 by binding to specific promoter sequences. Chromatin immunoprecipitation and electrophoretic mobility shift assays identified a DNA-binding motif inside the PTOV-A domain with similarities to known AT-hooks that specifically interacts with ALDH1A1 and CCNG2 promoters. Mutation of this AT-hook-like sequence significantly decreased the expression of ALDH1A1 and CCNG2 promoted by PTOV1. Immunohistochemistry revealed the association of PTOV1 with mitotic chromosomes in high grade prostate, colon, bladder, and breast carcinomas. Overexpression of PTOV1, ALDH1A1, and CCNG2 significantly correlated with poor prognosis in prostate carcinomas and with shorter relapse-free survival in colon carcinoma. The previously described interaction with translation complexes and its direct binding to ALDH1A1 and CCNG2 promoters found here reveal the PTOV1 capacity to modulate the ex-pression of critical genes at multiple levels in aggressive cancers. Remarkably, the AT-hook motifs in PTOV1 open possibilities for selective targeting its nuclear and/or cytoplasmic activities.