br In summary our findings
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.
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
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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.
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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
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.