DNA binding alters ARv7 dimer interactions

Özgün, Fatma; Kaya, Zeynep; Morova, Tunç; Geverts, Bart; Abraham, Tsion E; Houtsmuller, Adriaan B.; Royen, Martin E. van; Lack, Nathan A.

doi:10.1242/jcs.258332

Cited by 9 publications

(6 citation statements)

References 55 publications

(99 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While these data indicate that ARv7 does not act predominantly as a heterodimer with ARfl in VCaP16 cells, studies with ectopically expressed ARv7 clearly show it can act both as a homodimer and heterodimerize with ARfl (Kim et al, 2022;Ozgun et al, 2021;Roggero et al, 2021;Xu et al, 2015). A previous study in LNCaP95 cells (LNCaP cells adapted to androgen depleted medium) also found that DHT stimulation increased ARv7 chromatin binding, suggesting ARv7 heterodimerization with ARfl (Cato et al, 2019).…”

Section: Arv7 Binds Chromatin Independently Of Arflmentioning

confidence: 96%

Increased chromatin accessibility mediated by nuclear factor I drives transition to androgen receptor splice variant dependence in castration-resistant prostate cancer

Poluben,

Nouri,

Liang

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

Androgen receptor (AR) splice variants, of which ARv7 is the most common, are increased in prostate cancer (PC) that develops resistance to androgen signaling inhibitor drugs, but the extent to which these variants drive AR activity, and whether they have novel functions or dependencies, remain to be determined. We generated a subline of VCaP PC cells (VCaP16) that is resistant to the AR inhibitor enzalutamide (ENZ) and found that AR activity was independent of the full-length AR (ARfl), despite its continued high-level expression, and was instead driven by ARv7. The ARv7 cistrome and transcriptome in VCaP16 cells mirrored that of the ARfl in VCaP cells, although ARv7 chromatin binding was weaker, and strong ARv7 binding sites correlated with higher affinity ARfl binding sites across multiple models and clinical samples. Notably, although ARv7 expression in VCaP cells increased rapidly in response to ENZ, there was a long lag before it gained chromatin binding and transcriptional activity. This lag was associated with an increase in chromatin accessibility, with the AR and nuclear factor I (NFI) motifs being most enriched at these more accessible sites. Moreover, the transcriptional effects of combined NFIB and NFIX knockdown versus ARv7 knockdown were highly correlated. These findings indicate that ARv7 can drive the AR program, but that its activity is dependent on adaptations that increase chromatin accessibility to enhance its intrinsically weak chromatin binding.

show abstract

Section: Arv7 Binds Chromatin Independently Of Arflmentioning

confidence: 96%

Increased chromatin accessibility mediated by nuclear factor I drives transition to androgen receptor splice variant dependence in castration-resistant prostate cancer

Poluben,

Nouri,

Liang

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…20 different known AR-Vs which are truncated forms of the full-length AR (AR-FL) (Figure 2) (13, 16). Clinically relevant AR-Vs are almost always expressed with AR-FL and may coordinate gene expression via heterodimerisation (17,18). In the context of AR-FL, the LBD represses the AF1 function residing within the NTD when androgens are not bound to the LBD restricting its activation when the androgen trigger is absent (19).…”

Section: Ar Variantsmentioning

confidence: 99%

“…In most cases, AR-FL will homodimerise upon ligand activation and bind to DNA. Whilst it is widely agreed that AR-V7 will primarily heterodimerise with AR-FL, the protein can also homodimerise and have more transient DNA interactions (17,(37)(38)(39) (Figure 3). Özgün et al discovered that the genomic locations of heterodimers and AR-FL homodimers did not change but their chromatin binding dynamics were independent of each other (17), while AR-V7 homodimer DNAbinding locations have not been fully explored, although it has been determined that AR-Vs bind to constitutively open chromatin sites that are known to overlap AR-FL binding sites (40).…”

Section: Ar-v7mentioning

confidence: 99%

“…Whilst it is widely agreed that AR-V7 will primarily heterodimerise with AR-FL, the protein can also homodimerise and have more transient DNA interactions (17,(37)(38)(39) (Figure 3). Özgün et al discovered that the genomic locations of heterodimers and AR-FL homodimers did not change but their chromatin binding dynamics were independent of each other (17), while AR-V7 homodimer DNAbinding locations have not been fully explored, although it has been determined that AR-Vs bind to constitutively open chromatin sites that are known to overlap AR-FL binding sites (40). Although AR-FL and AR-V7 bind to similar response elements within the DNA, AR-V7 is not simply a constitutively active version of AR but has a unique cistrome, which can be used to experimentally quantify AR-V7 activity.…”

Section: Ar-v7mentioning

confidence: 99%

See 1 more Smart Citation

A compendium of Androgen Receptor Variant 7 target genes and their role in Castration Resistant Prostate Cancer

et al. 2023

View full text Add to dashboard Cite

Persistent androgen receptor (AR) signalling is the main driver of prostate cancer (PCa). Truncated isoforms of the AR called androgen receptor variants (AR-Vs) lacking the ligand binding domain often emerge during treatment resistance against AR pathway inhibitors such as Enzalutamide. This review discusses how AR-Vs drive a more aggressive form of PCa through the regulation of some of their target genes involved in oncogenic pathways, enabling disease progression. There is a pressing need for the development of a new generation of AR inhibitors which can repress the activity of both the full-length AR and AR-Vs, for which the knowledge of differentially expressed target genes will allow evaluation of inhibition efficacy. This review provides a detailed account of the most common variant, AR-V7, the AR-V7 regulated genes which have been experimentally validated, endeavours to understand their relevance in aggressive AR-V driven PCa and discusses the utility of the downstream protein products as potential drug targets for PCa treatment.

show abstract

“…AR-FL/AR-V7 heterodimers readily form in the nucleus via intermolecular N/C (NTD-LBD) interactions. However, DNA binding occupancy is determined by protein monomers, not homodimer or heterodimer complexes [20].…”

Section: Introductionmentioning

confidence: 99%

NanoLuc Binary Technology as a Methodological Approach: An Important New Tool for Studying the Localization of Androgen Receptor and Androgen Receptor Splice Variant V7 Homo- and Heterodimers

Guzman¹,

Weigelt²,

Neumann³

et al. 2023

Preprint

View full text Add to dashboard Cite

The androgen/androgen receptor (AR)-signaling axis plays a central role in the development and growth of prostate cancer (PCa) cells. Upon androgen-binding the AR dimerizes with another AR, translocates into the nucleus where the AR-dimer activates/inactivates androgen-dependent genes. In consequence treatments for locally advanced or metastatic PCa are commonly based on androgen deprivation therapies (ADT). Unfortunately, the clinical benefits of ADT are only transitory and most tumors develop mechanisms allowing the AR to bypass its need for physiological levels of circulating androgens. In the clinic failure of ADT is often characterized by the synthesis of a C-terminally truncated, constitutively active AR splice variant, termed AR-V7. In contrast to AR, the constitutively active AR-V7 does no longer need androgenic stimuli for nuclear entry and/or dimerization. The goal of the present study was to mechanistically decipher the interaction between full-length AR (AR-FL) and AR-V7 in AR-null HEK-293 cells using the NanoLuc Binary Technology (NanoBiT) structural complementation assay under androgen stimulation and deprivation conditions. Our data point toward a hypothesis that AR-FL/AR-FL homodimers form in the cytoplasm, whereas AR-V7/AR-V7 localize in the nucleus. However, after 15 min of androgen stimulation, all AR-FL/AR-FL, AR-FL/AR-V7 and AR-V7/AR-V7 dimers localized in the nucleus. In this way, we can show an androgen-regulated interaction between AR-FL and AR-V7 at forming heterodimers that localize in the nucleus, whereas AR-V7/AR-V7 dimers were found to localize in the absence of androgens in the nucleus. Treatment with enzalutamide diminished the luminescence of AR-FL homodimers and AR-FL/AR-V7 heterodimers but not AR-V7/AR-V7 homodimers.

show abstract

DNA binding alters ARv7 dimer interactions

Cited by 9 publications

References 55 publications

Increased chromatin accessibility mediated by nuclear factor I drives transition to androgen receptor splice variant dependence in castration-resistant prostate cancer

Increased chromatin accessibility mediated by nuclear factor I drives transition to androgen receptor splice variant dependence in castration-resistant prostate cancer

A compendium of Androgen Receptor Variant 7 target genes and their role in Castration Resistant Prostate Cancer

NanoLuc Binary Technology as a Methodological Approach: An Important New Tool for Studying the Localization of Androgen Receptor and Androgen Receptor Splice Variant V7 Homo- and Heterodimers

Contact Info

Product

Resources

About