Targeting androgen receptor phase separation to overcome antiandrogen resistance

Xie, Jingjing; He, Hao; Kong, Wenna; Li, Ziwen; Gao, Zhixuan; Xie, Daoqing; Sun, Lin; Fan, Xiaofei; Jiang, Xiangqing; Zheng, Qiangang; Guo, Li; Zhu, Jidong; Zhu, Guangya

doi:10.1038/s41589-022-01151-y

Cited by 66 publications

(67 citation statements)

References 55 publications

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“…1A). In agreement with recent findings 20 , we found that in transiently transfected HEK293T cells, both the full-length AR and the AR-V7 splice variant, that contain the AD and DBD, displayed the capacity to form nuclear clusters, but the DBD alone did not (Fig. 1B).…”

Section: Resultssupporting

confidence: 93%

“…Consistent with the in vitro data, eGFP-AR-ΔNLS that lacks the 23 FQNLF 27 motif formed fewer and smaller condensates in PC3 cells (Supplementary Fig. 4I-K), in agreement with recent reports 20 . These results collectively suggest that at least three interactions play key roles in phase separation of the hormone-exposed androgen receptor: i) interaction between the LBD and AD that requires helix formation by the 23 FQNLF 27 motif, ii) aromatic residues especially around the short helical regions in the Tau-5 sub-domain of the AD, and iii) the previously described dimerization interface in the LBD 51 (Fig.…”

Section: Short Unstable Helices Enhance Ar Phase Separationsupporting

confidence: 92%

“…To test the relevance of phase separation for AR function in cells, we expressed eGFP-tagged wild type full-length AR and mutants that contain the 8YtoS, 14YtoS and 22YtoS substitutions in the AD in AR-negative PC3 cells. Contrary to what is the case for WT 20 none of the YtoS mutants formed condensates upon DHT treatment (Fig. 2A).…”

Section: Ar Phase Separation Propensity Is Associated With Nuclear Tr...contrasting

confidence: 65%

“…Recent studies suggest that IDRs in many cellular proteins mediate liquid-liquid phase separation in vitro, and partitioning of the proteins into biomolecular condensates in cells [14][15][16] . Virtually all human TFs, including AR, contain an IDR, and these regions of sequence were recently shown to contribute to the formation of TF condensates and to the partitioning of TFs into heterotypic condensates with transcriptional effectors such as the Mediator co-activator or RNA Polymerase II [17][18][19][20] . The molecular basis of TF condensate interactions has only been dissected for a small number of TFs, but in all cases mutations of amino acids in the IDRs that altered phase separation also altered transcriptional activity 17,[21][22][23] .…”

Section: Introductionmentioning

confidence: 99%

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Rational optimization of a transcription factor activation domain inhibitor

Basu

Martínez-Cristóbal

Pesarrodona

et al. 2022

Preprint

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Transcription factors are among the most attractive therapeutic targets, but are considered largely undruggable. Here we provide evidence that small molecule-mediated partitioning of the androgen receptor, an oncogenic transcription factor, into phase-separated condensates has therapeutic effect in prostate cancer models. We show that the phase separation capacity of the androgen receptor is driven by aromatic residues and short unstable helices in its intrinsically disordered activation domain. Based on this knowledge, we developed tool compounds that covalently attach aromatic moieties to cysteines in the receptors' activation domain. The compounds enhanced partitioning of the receptor into condensates, facilitated degradation of the receptor, inhibited androgen receptor-dependent transcriptional programs, and had antitumorigenic effect in models of prostate cancer and castration-resistant prostate cancer in vitro and in vivo. These results establish a generalizable framework to target the phase-separation capacity of intrinsically disordered regions in oncogenic transcription factors and other disease-associated proteins with therapeutic intent.

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Section: Resultssupporting

confidence: 93%

Section: Short Unstable Helices Enhance Ar Phase Separationsupporting

confidence: 92%

Section: Ar Phase Separation Propensity Is Associated With Nuclear Tr...contrasting

confidence: 65%

Section: Introductionmentioning

confidence: 99%

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Rational optimization of a transcription factor activation domain inhibitor

Basu

Martínez-Cristóbal

Pesarrodona

et al. 2022

Preprint

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“…ETS-001 binds to the enzyme, blocking condensate formation and stifling the tumour. Last month, Zhu and his collaborators described another drug candidate for prostate cancer that disrupts condensates that are thought to make such cancers resistant to certain standard therapies 12 .…”

Section: Drugging Dropletsmentioning

confidence: 99%

The shape-shifting blobs that shook up cell biology

Dolgin¹

2022

Nature

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For years, if you asked a scientist how they pictured the inner workings of a cell, they might have spoken of a highly organized factory, with different departments each performing specialized tasks in delineated assembly lines.Ask now, and they might be more inclined to compare the cell to a chaotic openplan office, with hot-desking zones where different types of cellular matter gather to complete a task and then scatter to other regions.Everywhere scientists look in cells, throngs of proteins and RNA seem to be sticking together, coalescing into pearl-like droplets distinct from their surrounding environment. These dynamic compartments allow cells to perform essential functions, ranging from gene control and DNA repair to waste disposal and stress responses. They are often fleeting, and are unhindered by an enclosing membrane -unlike many other cellular components, such as mitochondria, which are membrane-bound. When a droplet is no longer needed, it vanishes.These transient beads are created by a MARINA FERIC & CLIFF BRANGWYNNECondensates (red, green, blue) containing proteins nest within one another in this fragment of a nucleus from a frog cell.

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Role of liquid–liquid phase separation in cancer: Mechanisms and therapeutic implications

Li,

2024

Cancer Innovation

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Liquid–liquid phase separation (LLPS) has emerged as a pivotal biological phenomenon involved in various cellular processes, including the formation of membrane‐less organelles and the regulation of biomolecular condensates through precise spatiotemporal coordination of signaling pathways in cells. Dysregulation of LLPSs results in aberrant biomolecular condensates, which are widely implicated in tumorigenesis and cancer progression. Here, we comprehensively summarize the multifaceted roles of LLPS in tumor biology from the perspective of cancer hallmarks, including genomic stability, metabolic reprogramming progression, ferroptosis, and metastasis, to unveil the intricate mechanisms by which LLPS occurs in tumorigenesis. We discuss current discoveries related to therapeutic involvement and potential clinical applications of LLPS in cancer treatment, highlighting the potential of targeting LLPS‐driven processes as novel therapeutic strategies. Additionally, we discuss the challenges associated with new approaches for cancer treatment based on LLPS. This in‐depth discussion of the impact of LLPS on fundamental aspects of tumor biology provides new insights into overcoming cancer.

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Targeting androgen receptor phase separation to overcome antiandrogen resistance

Cited by 66 publications

References 55 publications

Rational optimization of a transcription factor activation domain inhibitor

Rational optimization of a transcription factor activation domain inhibitor

The shape-shifting blobs that shook up cell biology

Role of liquid–liquid phase separation in cancer: Mechanisms and therapeutic implications

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