Related Experiment Video
Updated: May 25, 2026
Defining Gene Functions in Tumorigenesis by Ex vivo Ablation of Floxed Alleles in Malignant Peripheral Nerve Sheath Tumor Cells
Published on: August 25, 2021
Targeting pioneering factor and hormone receptor cooperative pathways to suppress tumor progression
Supriya Shah1, Shikha Prasad, Karen E Knudsen
1Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Abstract:
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 models mimicking disease progression. Curcumin cooperated in vivo with 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.
Insights
Curcumin, a compound from turmeric, suppresses prostate cancer growth by targeting androgen receptor (AR) signaling and altering chromatin. This natural compound offers a potential strategy for managing aggressive prostate tumors.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Prostate cancer progression involves nuclear receptors and pioneer factors, notably the androgen receptor (AR).
- Aggressive phenotypes and hormone therapy resistance are linked to elevated AR activity, coactivator p300, and pioneer factors like GATA2 and FOXA1.
- Targeting castrate-resistant AR activity and pioneer factor function is crucial for effective prostate cancer treatment.
Purpose of the Study:
- To investigate the potential of curcumin, a turmeric isoflavone, in suppressing AR and pioneer factor function in prostate cancer.
- To elucidate the mechanisms by which curcumin affects AR signaling and chromatin landscape.
- To evaluate the therapeutic efficacy of curcumin in preclinical models of prostate cancer.
Main Methods:
- Assessing curcumin's effect on p300 and CBP occupancy at AR binding sites.
- Analyzing histone acetylation and pioneer factor association with AR.
- Evaluating the impact of curcumin on AR target gene expression and chromatin accessibility.
- Testing curcumin's efficacy in combination with androgen deprivation in xenograft models.
Main Results:
- Curcumin suppresses p300 and CBP coactivator occupancy at AR target genes.
- Curcumin reduces histone acetylation and pioneer factor association, inhibiting AR binding and gene expression.
- Histone deacetylase inhibitors reverse curcumin's effects, confirming chromatin modification.
- Curcumin effectively suppresses ligand-dependent and ligand-independent AR activity, even in cells with high pioneer factor levels.
- In vivo studies show curcumin enhances androgen deprivation therapy, reducing tumor growth and delaying castrate resistance.
Conclusions:
- Curcumin targets both AR signaling and histone modification pathways in prostate cancer.
- Curcumin's ability to suppress AR and pioneer factor function presents a novel therapeutic strategy.
- Curcumin demonstrates potential as a novel agent for targeting AR signaling in prostate cancer, particularly in aggressive or resistant forms.
More Related Videos
07:48Utilizing Functional Genomics Screening to Identify Potentially Novel Drug Targets in Cancer Cell Spheroid Cultures
Published on: December 26, 2016
08:59Looking for Driver Pathways of Acquired Resistance to Targeted Therapy: Drug Resistant Subclone Generation and Sensitivity Restoring by Gene Knock-down
Published on: December 11, 2017
Related Concept Videos
02:57Targeted Cancer Therapies
There are several types of targeted therapies against specific...
02:57Targeted Cancer Therapies
There are several types of targeted therapies against specific...
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
01:19Interactions Between Signaling Pathways
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
02:38Mitogens and the Cell Cycle