Tumor and Stem Cell Biology Targeting Pioneering Factor and Hormone Receptor Cooperative Pathways to Suppress Tumor Progression
نویسندگان
چکیده
Nuclear receptors and pioneer factors drive the development and progression of prostate cancer. In this disease, aggressive disease phenotypes and hormone therapy failures result from resurgent activity of androgen receptor (AR) and the upregulation of coactivator protein p300 and pioneer factors (e.g., GATA2 and FOXA1). Thus, a major emphasis in the field is to identify mechanisms by which castrate-resistant AR activity and pioneer factor function can be combinatorially suppressed. Here we show that the turmeric spice isoflavone curcumin suppresses p300 and CBP occupancy at sites of AR function. Curcumin reduced the association of histone acetylation and pioneer factors, thereby suppressing AR residence and downstream target gene expression. Histone deacetylase inhibitors reversed the effects of curcumin on AR activity, further underscoring the impact of curcumin on altering the chromatin landscape. These functions precluded pioneer factor occupancy, leading ultimately to a suppression of ligand-dependent and ligand-independent AR residence on chromatin. Moreover, these functions were conserved even in cells with heightened pioneer factor activity, thus identifying a potential strategy to manage this subclass of tumors. Biological relevance was further identified using in vivo xenograft modelsmimicking disease progression. Curcumin cooperated in vivowith androgen deprivation as indicated by a reduction in tumor growth and delay to the onset of castrate-resistant disease. Together, our results show the combinatorial impact of targeting AR and histone modification in prostate cancer, thus setting the stage for further development of curcumin as a novel agent to target AR signaling. Cancer Res; 72(5); 1248–59. 2012 AACR.
منابع مشابه
STAT3 as a Key Factor in Tumor Microenvironment and Cancer Stem Cell
Background Recent studies revealed that tumor-associated macrophages (TAMs) play a decisive role in the regulation of tumor progression by manipulating tumor oncogenesis, angiogenesis and immune functions within tumor microenvironments. Signal transducer and activator of transcription 3 (STAT3), which is a point of convergence for numerous oncogenic signalling pathways, is constitutively activ...
متن کاملMiR-125b inhibits stromal cell proliferation in giant cell tumor of bone by targeting parathyroid hormone 1 receptor
Objective(s):miR-125b has been identified as a tumor suppressor in many tumors, but its role in giant cell tumor (GCT) of bone remains poorly understood. The current study aimed to investigate the potential role and mechanism of miR-125b in GCT. Materials and Methods:Expression levels of miR-125b in GCT tissues were determined using RT-PCR. The cell proliferation was surveyed by direct cell coun...
متن کاملTargeting pioneering factor and hormone receptor cooperative pathways to suppress tumor progression.
Nuclear receptors and pioneer factors drive the development and progression of prostate cancer. In this disease, aggressive disease phenotypes and hormone therapy failures result from resurgent activity of androgen receptor (AR) and the upregulation of coactivator protein p300 and pioneer factors (e.g., GATA2 and FOXA1). Thus, a major emphasis in the field is to identify mechanisms by which cas...
متن کاملCancer stem cells: therapeutic targets
Cancer stem cells (CSCs) have been identified as rare cellular populations in many cancers, including leukemia and solid tumors. This minor subpopulation of cancerous cells is immortal tumor-initiating cells which thought to be responsible for cancer initiation, progression, metastasis, recurrence and drug/radiation resistance. Low proliferative rate, high self-renewing capacity, differentiatio...
متن کاملBiological and Clinicopathological Significance of Cripto-1 Expression in the Progression of Human ESCC
Background: Human Cripto-1, a member of the EGF-CFC family, is involved in embryonic development, embryonic stem cell maintenance, and tumor progression. It also participates in multiple cell signaling pathways including Wnt, Notch, and TGF-β. Remarkably, it is expressed in cancer stem cell (CSC) compartments, boosting tumor cell migration, invasion, and angiogenesis. Although Cripto-1 is ...
متن کامل