Small-molecule inhibitor targeting orphan nuclear receptor COUP-TFII for prostate cancer treatment

Wang, Leiming; Cheng, Chiang-Min; Qin, Jun; Xu, Mafei; Kao, Chung‐Yao; Shi, Jingjing; You, Erli; Gong, Wanchun; Rosa, Laura Pedro; Chase, Peter; Scampavia, Louis; Madoux, Franck; Spicer, Timothy; Hodder, Peter; Xu, Huijuan; Tsai, Sophia Y.; Tsai, Ming‐Jer

doi:10.1126/sciadv.aaz8031

Cited by 16 publications

(11 citation statements)

References 33 publications

(55 reference statements)

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“…Our results clearly support the essential role of COUP-TFII in the development of enzalutamide resistance via regulation of YAP1 function. Since specific COUP-TFII inhibitor has been recently identified and shown the therapeutic potential in PCa [ 33 ], it will be expected to test its efficacy for overcoming enzalutamide resistance in the future.…”

Section: Discussionmentioning

confidence: 99%

YAP1 overexpression contributes to the development of enzalutamide resistance by induction of cancer stemness and lipid metabolism in prostate cancer

Lee

Huang

et al. 2021

Oncogene

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Metastatic castration-resistant prostate cancer (mCRPC) is a malignant and lethal disease caused by relapse after androgen-deprivation (ADT) therapy. Since enzalutamide is innovated and approved by US FDA as a new treatment option for mCRPC patients, drug resistance for enzalutamide is a critical issue during clinical usage. Although several underlying mechanisms causing enzalutamide resistance were previously identified, most of them revealed that drug resistant cells are still highly addicted to androgen and AR functions. Due to the numerous physical functions of AR in men, innovated AR-independent therapy might alleviate enzalutamide resistance and prevent production of adverse side effects. Here, we have identified that yes-associated protein 1 (YAP1) is overexpressed in enzalutamide-resistant (EnzaR) cells. Furthermore, enzalutamide-induced YAP1 expression is mediated through the function of chicken ovalbumin upstream promoter transcription factor 2 (COUP-TFII) at the transcriptional and the post-transcriptional levels. Functional analyses reveal that YAP1 positively regulates numerous genes related to cancer stemness and lipid metabolism and interacts with COUP-TFII to form a transcriptional complex. More importantly, YAP1 inhibitor attenuates the growth and cancer stemness of EnzaR cells in vitro and in vivo. Finally, YAP1, COUP-TFII, and miR-21 are detected in the extracellular vesicles (EVs) isolated from EnzaR cells and sera of patients. In addition, treatment with EnzaR-EVs induces the abilities of cancer stemness, lipid metabolism and enzalutamide resistance in its parental cells. Taken together, these results suggest that YAP1 might be a crucial factor involved in the development of enzalutamide resistance and can be an alternative therapeutic target in prostate cancer.

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Section: Discussionmentioning

confidence: 99%

YAP1 overexpression contributes to the development of enzalutamide resistance by induction of cancer stemness and lipid metabolism in prostate cancer

Lee

Huang

et al. 2021

Oncogene

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“…The present results point to an efficient interaction between the COUP-TFII isoforms that confers an advantage in terms of PDAC progression and dissemination. The recent demonstration that COUP-TFII is modulated by small molecules ( 52 ) suggests that this nuclear receptor system is druggable and potentially a new therapeutic target for PDAC.…”

Section: Discussionmentioning

confidence: 99%

Isoforms of the orphan nuclear receptor COUP‑TFII differentially modulate pancreatic cancer progression

et al. 2022

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The expression of the nuclear receptor transcription factor (TF) COUP-TFII is broadly associated with cell differentiation and cancer development, including of pancreatic ductal adenocarcinoma (PDAC), a devastating disease with one of the poorest prognoses among cancers worldwide. Recent studies have started to investigate the pathological and physiological roles of a novel COUP-TFII isoform (COUP-TFII_V2) that lacks the DNA-binding domain. As the role of the canonical COUP-TFII in PDAC was previously demonstrated, the present study evaluated whether COUP-TFII_V2 may have a functional role in PDAC. It was demonstrated that COUP-TFII_V2 naturally occurs in PDAC cells and in primary samples, where its expression is consistent with shorter overall survival and peripheral invasion. Of note, COUP-TFII_V2, exhibiting nuclear and cytosolic expression, is linked to epithelial to mesenchymal transition (EMT) and cancer progression, as confirmed by nude mouse experiments. The present results demonstrated that COUP-TFII_V2 distinctively regulates the EMT of PDAC and, similarly to its sibling, it is associated with tumor aggressiveness. The two isoforms have both overlapping and exclusive functions that cooperate with cancer growth and dissemination. By studying how PDAC cells switch from one isoform to the other, novel insight into cancer biology was gained, indicating that this receptor may serve as a novel possible target for PDAC management.

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“…Structural data suggest that the COUP-TFII protein is capable of an autorepressive conformation, due to side chain amino acids occupying its own ligand pocket [ 119 ]. Nevertheless, it can be activated by supraphysiological concentration of retinoids and synthetic agonists and antagonist of COUP-TFII have been recently published [ 120 , 121 , 122 ]. COUP-TFII is essential for many biological processes, as demonstrated by the early embryonic lethality (around E9.5–E10) of COUP-TFII knock-out mice [ 118 ].…”

Section: Orphan Nuclear Receptorsmentioning

confidence: 99%

Role of Nuclear Receptors in Controlling Erythropoiesis

Pastori

Pozzi

Labedz

et al. 2022

IJMS

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Nuclear receptors (NRs), are a wide family of ligand-regulated transcription factors sharing a common modular structure composed by an N-terminal domain and a ligand-binding domain connected by a short hinge linker to a DNA-binding domain. NRs are involved in many physiological processes, including metabolism, reproduction and development. Most of them respond to small lipophilic ligands, such as steroids, retinoids, and phospholipids, which act as conformational switches. Some NRs are still “orphan” and the search for their ligands is still ongoing. Upon DNA binding, NRs can act both as transcriptional activators or repressors of their target genes. Theoretically, the possibility to modulate NRs activity with small molecules makes them ideal therapeutic targets, although the complexity of their signaling makes drug design challenging. In this review, we discuss the role of NRs in erythropoiesis, in both homeostatic and stress conditions. This knowledge is important in view of modulating red blood cells production in disease conditions, such as anemias, and for the expansion of erythroid cells in culture for research purposes and for reaching the long-term goal of cultured blood for transfusion.

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Small-molecule inhibitor targeting orphan nuclear receptor COUP-TFII for prostate cancer treatment

Cited by 16 publications

References 33 publications

YAP1 overexpression contributes to the development of enzalutamide resistance by induction of cancer stemness and lipid metabolism in prostate cancer

YAP1 overexpression contributes to the development of enzalutamide resistance by induction of cancer stemness and lipid metabolism in prostate cancer

Isoforms of the orphan nuclear receptor COUP‑TFII differentially modulate pancreatic cancer progression

Role of Nuclear Receptors in Controlling Erythropoiesis

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