Pioneer of prostate cancer: past, present and the future of FOXA1

Teng, Mona; Zhou, Stanley; Cai, Changmeng; Lupien, Mathieu; He, Housheng Hansen

doi:10.1007/s13238-020-00786-8

Cited by 99 publications

(77 citation statements)

References 71 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, beyond FOXC transcription factors, a variety of other Forkhead box proteins have recently been the focus of research regarding their key role in EMT and cancer progression. FOXA1 is considered a pioneer factor of PCa onset and progression, through induction of open chromatin conformations that allow binding of several transcription factors, mainly the AR in both normal and cancerous prostate cells [ 160 ]. Another AR-independent pathway allows coding and noncoding mutations of FOXA1 to promote EMT.…”

Section: Molecular Events Governing Emt In Cancer Progressionmentioning

confidence: 99%

Cell Plasticity and Prostate Cancer: The Role of Epithelial–Mesenchymal Transition in Tumor Progression, Invasion, Metastasis and Cancer Therapy Resistance

Papanikolaou

Vourda

Syggelos

et al. 2021

Cancers

View full text Add to dashboard Cite

Prostate cancer, the second most common malignancy in men, is characterized by high heterogeneity that poses several therapeutic challenges. Epithelial–mesenchymal transition (EMT) is a dynamic, reversible cellular process which is essential in normal embryonic morphogenesis and wound healing. However, the cellular changes that are induced by EMT suggest that it may also play a central role in tumor progression, invasion, metastasis, and resistance to current therapeutic options. These changes include enhanced motility and loss of cell–cell adhesion that form a more aggressive cellular phenotype. Moreover, the reverse process (MET) is a necessary element of the metastatic tumor process. It is highly probable that this cell plasticity reflects a hybrid state between epithelial and mesenchymal status. In this review, we describe the underlying key mechanisms of the EMT-induced phenotype modulation that contribute to prostate tumor aggressiveness and cancer therapy resistance, in an effort to provide a framework of this complex cellular process.

show abstract

Section: Molecular Events Governing Emt In Cancer Progressionmentioning

confidence: 99%

Cell Plasticity and Prostate Cancer: The Role of Epithelial–Mesenchymal Transition in Tumor Progression, Invasion, Metastasis and Cancer Therapy Resistance

Papanikolaou

Vourda

Syggelos

et al. 2021

Cancers

View full text Add to dashboard Cite

show abstract

“…FOXA-1 (forkhead box A1) is another pioneer transcription factor involved in AR-promoted gene transcription. It was demonstrated to play a key role in AR-mediated tumor growth and progression in CRPC cells [ 108 ]. Mechanistically, FOXA1 binds to AR and the transcription factor HOXB13 at the cytoplasmic level; then, the FOXA1-AR-HOXB13 complex translocates into the nucleus where it binds, with the cooperation of GATA2, to specific DNA sequences.…”

Section: The Androgen/ar Axis In Crpcmentioning

confidence: 99%

“…Mechanistically, FOXA1 binds to AR and the transcription factor HOXB13 at the cytoplasmic level; then, the FOXA1-AR-HOXB13 complex translocates into the nucleus where it binds, with the cooperation of GATA2, to specific DNA sequences. FOXA1, HOXB13 and GATA2 open compacted chromatin, increasing the accessibility of these DNA regions to additional transcription factors, thus promoting AR transcriptional activity and the expression of AR-regulated genes [ 42 , 108 , 109 , 110 ].…”

Section: The Androgen/ar Axis In Crpcmentioning

confidence: 99%

Dissecting the Hormonal Signaling Landscape in Castration-Resistant Prostate Cancer

Fontana

Limonta

2021

Cells

View full text Add to dashboard Cite

Understanding the molecular mechanisms underlying prostate cancer (PCa) progression towards its most aggressive, castration-resistant (CRPC) stage is urgently needed to improve the therapeutic options for this almost incurable pathology. Interestingly, CRPC is known to be characterized by a peculiar hormonal landscape. It is now well established that the androgen/androgen receptor (AR) axis is still active in CRPC cells. The persistent activity of this axis in PCa progression has been shown to be related to different mechanisms, such as intratumoral androgen synthesis, AR amplification and mutations, AR mRNA alternative splicing, increased expression/activity of AR-related transcription factors and coregulators. The hypothalamic gonadotropin-releasing hormone (GnRH), by binding to its specific receptors (GnRH-Rs) at the pituitary level, plays a pivotal role in the regulation of the reproductive functions. GnRH and GnRH-R are also expressed in different types of tumors, including PCa. Specifically, it has been demonstrated that, in CRPC cells, the activation of GnRH-Rs is associated with a significant antiproliferative/proapoptotic, antimetastatic and antiangiogenic activity. This antitumor activity is mainly mediated by the GnRH-R-associated Gαi/cAMP signaling pathway. In this review, we dissect the molecular mechanisms underlying the role of the androgen/AR and GnRH/GnRH-R axes in CRPC progression and the possible therapeutic implications.

show abstract

“…Genomic aberrations cooperate with epigenetic modifiers, such as REST, 8 and neurolineage pioneering transcription factors, such as BRN2, 9 ONECUT2, 10 SRRM4, 11 and MYCN 12 drive the emergence of NEPC. Loss of luminal lineage transcription factors, such as AR and FOXA1 breaches the barriers of prostate adenocarcinoma (AdPC) reprogramming 13 . However, the evolution of NEPC is a complex process and a spectrum of intermediate differentiation states constitute a continuum between the AdPC and NEPC phenotypes; therefore, the underlying molecular mechanisms remain largely elusive, and druggable targets for clinical application need to be identified.…”

Section: Introductionmentioning

confidence: 99%

“…Loss of luminal lineage transcription factors, such as AR and FOXA1 breaches the barriers of prostate adenocarcinoma (AdPC) reprogramming. 13 However, the evolution of NEPC is a complex process and a spectrum of intermediate differentiation states constitute a continuum between the AdPC and NEPC phenotypes; therefore, the underlying molecular mechanisms remain largely elusive, and druggable targets for clinical application need to be identified. Smoothened (SMO) is a class Frizzled (Class F) G proteincoupled receptor that is a key signal transducer of the Hedgehog (Hh) pathway.…”

Section: Introductionmentioning

confidence: 99%

Smoothened loss is a characteristic of neuroendocrine prostate cancer

Wang

et al. 2021

The Prostate

View full text Add to dashboard Cite

Purpose Hedgehog (Hh) signaling promotes castration‐resistant prostate cancer by supporting androgen‐independent prostate cancer cell development and growth; however, its role in neuroendocrine prostate cancer (NEPC) has not yet been explored. In this study, we assessed the expression of key genes involved in Hh signaling in prostate cancer and investigated the potential role of smoothened (SMO) in the pathogenesis of NEPC. Methods Six public datasets, each containing cases of prostate adenocarcinoma (AdPC) and NEPC, were analyzed to compare the differential messenger RNA (mRNA) expression of six classic Hh signaling genes. The SMO, synaptophysin, chromogranin A (CHGA) and androgen receptor (AR) proteins were evaluated in human tissues from 5 cases of NEPC, 2 cases of AdPC mixed with NEPC, 2 cases of AdPC with neuroendocrine differentiation and 22 cases of high‐grade AdPC as determined by an immunohistochemistry assay. Gene set enrichment analysis (GSEA) was performed to identify relevant genetic signatures associated with SMO expression based on the public datasets. Stable SMO‐knockdown LNCaP and C4‐2B cells were established with a lentiviral system, and the expression of SMO, Gli1, AR, prostate‐specific antigen (PSA), and REST was assessed by real‐time polymerase chain reaction and western blot. Secreted PSA in the conditioned medium was assessed by ELISA. Gli1 was ectopically expressed performed by the transfection of Gli1 complementary DNA into SMO‐knockdown LNCaP cells, and western blot was used to assess of AR and PSA expression. Results The mRNA level of SMO was dramatically downregulated in NEPC samples compared with AdPC samples in all 6 public datasets. SMO protein loss was observed in 100% of NEPC samples but in only 9% (2 of 22) of high‐grade AdPC samples. GSEA results showed that SMO loss was closely correlated with AR signaling activity. Stable SMO knockdown significantly attenuated AR signaling activity and suppressed AR expression, while Gli1 overexpression partially reversed the inhibitory effects of SMO knockdown on AR signaling activity and AR expression in LNCaP and C4‐2B cells. Conclusion These results demonstrate that SMO loss is a characteristic of NEPC and that detecting SMO by IHC could aid pathologists in NEPC diagnosis. SMO loss may promote NEPC pathogenesis by modulating AR signaling.

show abstract

Pioneer of prostate cancer: past, present and the future of FOXA1

Cited by 99 publications

References 71 publications

Cell Plasticity and Prostate Cancer: The Role of Epithelial–Mesenchymal Transition in Tumor Progression, Invasion, Metastasis and Cancer Therapy Resistance

Cell Plasticity and Prostate Cancer: The Role of Epithelial–Mesenchymal Transition in Tumor Progression, Invasion, Metastasis and Cancer Therapy Resistance

Dissecting the Hormonal Signaling Landscape in Castration-Resistant Prostate Cancer

Smoothened loss is a characteristic of neuroendocrine prostate cancer

Contact Info

Product

Resources

About