In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 2832-2832
Abstract:
(a) introductory sentence indicating the purposes of the study Metastasis formation is associated with poor patient prognosis. Epithelial-mesenchymal and mesenchymal-epithelial (EMT/MET) transition cycles are key for the formation, survival, and homing of metastatic cells. Inhibitors against epigenetic modulators of the histone deacetylase family (HDACi) are promising, clinically tested epigenetic drugs that may combat cancer proliferation and spread. (b) brief description of pertinent experimental procedures We chose a systems toxicology approach to analyze the relevance of HDACs and their inhibitors for metastatic cell growth. We combined in vivo tests with morphological, cellular, functional, and global proteomic analyses. This strategy follows the 3R principle by Russel and Burch. Of the four classes of HDACs (I-IV), the class I subgroup is most important for tumorigenesis. We therefore analyzed how the pharmacological inhibition of class I HDACs affects the growth and spreading of syngeneic kidney cancer cells into the lungs of BALB/c mice and how such drugs affect tumor cell growth, apoptosis, migration, and gene expression patterns controlling EMT/MET in transformed kidney and breast cells. Furthermore, we investigated how the genetic elimination of HDACs affects cancer cell growth and EMT/MET. We used flow cytometry, immunoblot, immunofluorescence, qPCR, proteomics on a global scale, RNAi against the class I HDACs HDAC1/HDAC2, and in vivo tumor analyses. (c) summary of the new, unpublished data Both the inhibition as well as the elimination of HDAC1/HDAC2 evokes growth arrest, morphological alterations, and apoptosis. HDACi block tumor cell migration, integrin-dependent cell adhesion, and EMT induced by the cytokine TGF-β. Global proteomics and qPCR analyses illustrate that HDACi disrupt EMT/MET cycles and metastatic spread. Moreover, these assays reveal pathways through which HDACi propel cancer cell apoptosis. (d) statement of the conclusions Class I HDACi can modulate the EMT/MET balance that is required for the detrimental process of metastasis. Hence, HDACi should be considered further as clinical treatment option. Citation Format: Oliver H. Krämer, Nicole Kiweler. Class I histone deacetylase inhibitors impair tumor growth and metastatic programs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2832. doi:10.1158/1538-7445.AM2017-2832
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2017-2832
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2017
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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