The androgen receptor (AR) plays a crucial role in normal physiology, development and metabolism as well as in the aetiology and treatment of diverse pathologies such as androgen insensitivity ...syndromes (AIS), male infertility and prostate cancer (PCa). Here we show that dimerization of AR ligand-binding domain (LBD) is induced by receptor agonists but not by antagonists. The 2.15-Å crystal structure of homodimeric, agonist- and coactivator peptide-bound AR-LBD unveils a 1,000-Å
large dimerization surface, which harbours over 40 previously unexplained AIS- and PCa-associated point mutations. An AIS mutation in the self-association interface (P767A) disrupts dimer formation in vivo, and has a detrimental effect on the transactivating properties of full-length AR, despite retained hormone-binding capacity. The conservation of essential residues suggests that the unveiled dimerization mechanism might be shared by other nuclear receptors. Our work defines AR-LBD homodimerization as an essential step in the proper functioning of this important transcription factor.
Androgen deprivation is the mainstay therapy for metastatic prostate cancer (PCa). Another way of suppressing androgen receptor (AR) signaling is via AR antagonists or antiandrogens. Despite being ...frequently prescribed in clinical practice, there is conflicting evidence concerning the role of AR antagonists in the management of PCa. In the castration-resistant settings of PCa, docetaxel has been the only treatment option for decades. With recent evidence that castration-resistant PCa is far from AR-independent, there has been an increasing interest in developing new AR antagonists. This review gives a concise overview of the clinically available antiandrogens and the experimental AR antagonists that tackle androgen action with a different approach.
The majority of prostate cancers are hormone-dependent at diagnosis highlighting the central role of androgen signalling in this disease. Surprisingly, most forms of castration-resistant prostate ...cancer (CRPC) are still dependent on the androgen receptor (AR) for survival. Therefore, the advent of new AR-targeting drugs, such as enzalutamide, is certainly beneficial for the many patients with metastatic CRPC. Indeed, this compound provides a substantial survival benefit-but it is not curative. This Perspectives article describes the different ways through which cancer cells can become resistant to enzalutamide, such as AR truncation and other mutations, as well as by-pass of the AR dependence of prostate cancer cells through expression of the glucocorticoid receptor. The clinical relevance of these mechanisms and emerging questions concerning new therapeutic regimens in the treatment of metastatic CRPC are being discussed.
Abstract
The glucocorticoid receptor (GR) regulates gene expression, governing aspects of homeostasis, but is also involved in cancer. Pharmacological GR activation is frequently used to alleviate ...therapy-related side-effects. While prior studies have shown GR activation might also have anti-proliferative action on tumours, the underpinnings of glucocorticoid action and its direct effectors in non-lymphoid solid cancers remain elusive. Here, we study the mechanisms of glucocorticoid response, focusing on lung cancer. We show that GR activation induces reversible cancer cell dormancy characterised by anticancer drug tolerance, and activation of growth factor survival signalling accompanied by vulnerability to inhibitors. GR-induced dormancy is dependent on a single GR-target gene,
CDKN1C
, regulated through chromatin looping of a GR-occupied upstream distal enhancer in a SWI/SNF-dependent fashion. These insights illustrate the importance of GR signalling in non-lymphoid solid cancer biology, particularly in lung cancer, and warrant caution for use of glucocorticoids in treatment of anticancer therapy related side-effects.
Androgen receptor (AR) inhibitors represent the mainstay of prostate cancer treatment. In a genome-wide CRISPR-Cas9 screen using LNCaP prostate cancer cells, loss of co-repressor
conferred resistance ...to AR antagonists apalutamide and enzalutamide. Genes differentially expressed upon
loss share AR as the top transcriptional regulator, and
loss rescued the expression of a subset of androgen-responsive genes upon enzalutamide treatment. GR expression was strongly upregulated upon AR inhibition in a
-negative background. This was consistent with binding of TLE3 and AR at the
locus. Furthermore, GR binding was observed proximal to TLE3/AR-shared genes. GR inhibition resensitized
cells to enzalutamide. Analyses of patient samples revealed an association between TLE3 and GR levels that reflected our findings in LNCaP cells, of which the clinical relevance is yet to be determined. Together, our findings reveal a mechanistic link between TLE3 and GR-mediated resistance to AR inhibitors in human prostate cancer.
Sex hormones and their receptors play a crucial role in human sexual dimorphism and have been traditionally associated with hormone-dependent cancers like breast, prostate, and endometrial cancer. ...However, recent research has broadened our understanding by revealing connections with other types of cancers, such as lung cancer, where the androgen receptor has been found to be particularly significant. This review aims to explore the molecular mechanisms of androgen action in lung cancer pathogenesis and progression, highlighting the potential of inhibiting the androgen receptor signaling pathway as a therapeutic strategy for lung cancer treatment.
Abstract
The small intestine is a rapidly proliferating organ that is maintained by a small population of
Lgr5
-expressing intestinal stem cells (ISCs). However, several
Lgr5
-negative ISC ...populations have been identified, and this remarkable plasticity allows the intestine to rapidly respond to both the local environment and to damage. However, the mediators of such plasticity are still largely unknown. Using intestinal organoids and mouse models, we show that upon ribosome impairment (driven by
Rptor
deletion, amino acid starvation, or low dose cyclohexamide treatment) ISCs gain an
Lgr5
-negative, fetal-like identity. This is accompanied by a rewiring of metabolism. Our findings suggest that the ribosome can act as a sensor of nutrient availability, allowing ISCs to respond to the local nutrient environment. Mechanistically, we show that this phenotype requires the activation of ZAKɑ, which in turn activates YAP, via SRC. Together, our data reveals a central role for ribosome dynamics in intestinal stem cells, and identify the activation of ZAKɑ as a critical mediator of stem cell identity.
Glucocorticoid receptor (GR) is a transcription factor that plays a crucial role in cancer biology. In this study, we utilized an in silico‐designed GR activity signature to demonstrate that GR ...relates to the proliferative capacity of numerous primary cancer types. In breast cancer, the GR activity status determines luminal subtype identity and has implications for patient outcomes. We reveal that GR engages with estrogen receptor (ER), leading to redistribution of ER on the chromatin. Notably, GR activation leads to upregulation of the ZBTB16 gene, encoding for a transcriptional repressor, which controls growth in ER‐positive breast cancer and associates with prognosis in luminal A patients. In relation to ZBTB16's repressive nature, GR activation leads to epigenetic remodeling and loss of histone acetylation at sites proximal to cancer‐driving genes. Based on these findings, epigenetic inhibitors reduce viability of ER‐positive breast cancer cells that display absence of GR activity. Our findings provide insights into how GR controls ER‐positive breast cancer growth and may have implications for patients' prognostication and provide novel therapeutic candidates for breast cancer treatment.
Synopsis
Activity of the Glucocorticoid Receptor across various cancer types is inversely related to proliferative signatures. In breast cancer, heightened Glucocorticoid Receptor (GR) activity correlates with improved patient outcomes and is linked to the regulation of the tumor suppressor ZBTB16.
GR activity correlates negatively with proliferative capacity across various cancer types.
In breast cancer, a distinct link is observed between GR activity status and luminal subtype identity, influencing patient outcomes.
Hormone‐regulated gene ZBTB16, is pivotal in controlling the growth of ER‐positive breast cancer.
Significant epigenetic changes accompanied GR activation, including diminished histone acetylation near cancer‐driving genes.
The insights gained suggest potential novel therapeutic candidates and advanced patient prognostication methods in breast cancer treatment.
Activity of the glucocorticoid receptor across various cancer types is inversely related to proliferative signatures. In breast cancer, heightened glucocorticoid receptor (GR) activity correlates with improved patient outcomes and is linked to the regulation of the tumor suppressor ZBTB16.
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