Novel Androgen Receptor Coregulator GRHL2 Exerts Both Oncogenic and Antimetastatic Functions in Prostate Cancer

Paltoglou, Steve M; Das, Rajdeep; Townley, Scott L.; Hickey, Theresa E.; Tarulli, Gerard A.; Coutinho, Isabel; Fernandes, Rayzel C.; Hanson, Adrienne R.; Denis, Iza; Carroll, Jason S.; Dehm, Scott M.; Raj, Ganesh V.; Plymate, Stephen R.; Tilley, Wayne D.; Selth, Luke A.

doi:10.1158/0008-5472.can-16-1616

Cited by 81 publications

(71 citation statements)

References 48 publications

(66 reference statements)

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“…GRHL2 suppresses EMT and has an expression pattern inversely correlated with that of ZEB1 in numerous cancers (Chen et al, 2016;Chung et al, 2016;Nishino et al, 2017;Paltoglou et al, 2017;Pan et al, 2017;Quan et al, 2014;Werner et al, 2013;Xiang et al, 2017). The miR-200 family of microRNAs, including MIR141, MIR200A, MIR200B, MIR200C and MIR429, along with MIR205, bind to the ZEB1 and ZEB2 mRNAs and inhibit their translation (Gregory et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Inactivation of Zeb1 in GRHL2-deficient mouse embryos rescues mid-gestation viability and secondary palate closure

Carpinelli

Vries

Auden

et al. 2020

Disease Models &Amp; Mechanisms

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Cleft lip and palate are common birth defects resulting from failure of the facial processes to fuse during development. The mammalian grainyhead-like (Grhl1-3) genes play key roles in a number of tissue fusion processes including neurulation, epidermal wound healing and eyelid fusion. One family member, Grhl2, is expressed in the epithelial lining of the first pharyngeal arch in mice at embryonic day (E)10.5, prompting analysis of the role of this factor in palatogenesis. Grhl2null mice die at E11.5 with neural tube defects and a cleft face phenotype, precluding analysis of palatal fusion at a later stage of development. However, in the first pharyngeal arch of Grhl2-null embryos, dysregulation of transcription factors that drive epithelialmesenchymal transition (EMT) occurs. The aberrant expression of these genes is associated with a shift in RNA-splicing patterns that favours the generation of mesenchymal isoforms of numerous regulators. Driving the EMT perturbation is loss of expression of the EMT-suppressing transcription factors Ovol1 and Ovol2, which are direct GRHL2 targets. The expression of the miR-200 family of microRNAs, also GRHL2 targets, is similarly reduced, resulting in a 56-fold upregulation of Zeb1 expression, a major driver of mesenchymal cellular identity. The critical role of GRHL2 in mediating cleft palate in Zeb1 −/− mice is evident, with rescue of both palatal and facial fusion seen in Grhl2 −/− ;Zeb1 −/− embryos. These findings highlight the delicate balance between GRHL2/ZEB1 and epithelial/mesenchymal cellular identity that is essential for normal closure of the palate and face. Perturbation of this pathway may underlie cleft palate in some patients.

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Section: Discussionmentioning

confidence: 99%

Inactivation of Zeb1 in GRHL2-deficient mouse embryos rescues mid-gestation viability and secondary palate closure

Carpinelli

Vries

Auden

et al. 2020

Disease Models &Amp; Mechanisms

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“…New technologies such as rapid immunoprecipitation mass spectrometry of endogenous protein (RIME) (Mohammed et al 2013) led to increased knowledge of the AR-enhanceosome -the protein complex at AR-bound enhancers. We and others have identified novel AR protein interactions in prostate cancer cell lines (Paltoglou et al 2017, Stelloo et al 2018a; however, the functional impact of all newly identified AR interaction partners still needs to be unraveled. A recently developed technique, quantitative multiplexed method (qPLEX-RIME) (Papachristou et al 2018), may shed light on the composition of these AR multiprotein complexes in human tissue samples.…”

Section: Othersmentioning

confidence: 99%

Androgen receptor enhancer usage and the chromatin regulatory landscape in human prostate cancers

Stelloo

Bergman

Zwart

2019

Endocrine-Related Cancer

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The androgen receptor (AR) is commonly known as a key transcription factor in prostate cancer development, progression and therapy resistance. Genome-wide chromatin association studies revealed that transcriptional regulation by AR mainly depends on binding to distal regulatory enhancer elements that control gene expression through chromatin looping to gene promoters. Changes in the chromatin epigenetic landscape and DNA sequence can locally alter AR-DNA-binding capacity and consequently impact transcriptional output and disease outcome. The vast majority of reports describing AR chromatin interactions have been limited to cell lines, identifying numerous other factors and interacting transcription factors that impact AR chromatin interactions. Do these factors also impact AR cistromics – the genome-wide chromatin-binding landscape of AR – in vivo? Recent technological advances now enable researchers to identify AR chromatin-binding sites and their target genes in human specimens. In this review, we provide an overview of the different factors that influence AR chromatin binding in prostate cancer specimens, which is complemented with knowledge from cell line studies. Finally, we discuss novel perspectives on studying AR cistromics in clinical samples.

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“…LNCaP cells were seeded at 3 × 10 6 cells/plate in 15 cm plates in RPMI-1640 medium containing 10% DCC-FBS for 3 days, then treated for 4 hours with 10 nM DHT or Vehicle (ethanol). AR ChIP was performed as described previously (86).…”

Section: Chromatin Immunoprecipitation (Chip)mentioning

confidence: 99%

DECR1 is an androgen-repressed survival factor that regulates PUFA oxidation to protect prostate tumor cells from ferroptosis

Nassar

Mah

Dehairs

et al. 2019

Preprint

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Fatty acidβ -oxidation (FAO) is the main bioenergetic pathway in prostate cancer (PCa) and a promising novel therapeutic vulnerability. Here we demonstrate therapeutic efficacy of targeting FAO in clinical prostate tumors cultured ex vivo, and identify DECR1, which encodes the rate-limiting enzyme for oxidation of polyunsaturated fatty acids (PUFAs), as robustly overexpressed in PCa tissues and associated with shorter relapse-free survival.DECR1 is a negatively-regulated androgen receptor (AR) target gene and, therefore, may promote PCa cell survival and resistance to AR targeting therapeutics. DECR1 knockdown in PCa cells selectively inhibited β -oxidation of PUFAs, inhibited proliferation and migration of PCa cells, including treatment resistant lines, and suppressed tumor cell proliferation in vivo.Mechanistically, targeting of DECR1 caused cellular accumulation of linoleic acid, enhanced mitochondrial oxidative stress and lipid peroxidation, and ferroptosis. These findings implicate PUFA oxidation via DECR1 as a previously unexplored facet of FAO that promotes survival of PCa cells.

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Novel Androgen Receptor Coregulator GRHL2 Exerts Both Oncogenic and Antimetastatic Functions in Prostate Cancer

Cited by 81 publications

References 48 publications

Inactivation of Zeb1 in GRHL2-deficient mouse embryos rescues mid-gestation viability and secondary palate closure

Inactivation of Zeb1 in GRHL2-deficient mouse embryos rescues mid-gestation viability and secondary palate closure

Androgen receptor enhancer usage and the chromatin regulatory landscape in human prostate cancers

DECR1 is an androgen-repressed survival factor that regulates PUFA oxidation to protect prostate tumor cells from ferroptosis

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