The expression of YAP1 is increased in high-grade prostatic adenocarcinoma but is reduced in neuroendocrine prostate cancer

Cheng, Siyuan; Prieto-Domínguez, Néstor; Yang, Shu; Connelly, Zachary M.; StPierre, Samantha; Rushing, Bryce; Watkins, Andy; Shi, Lawrence; Lakey, Meredith A.; Baiamonte, Lyndsey Buckner; Fazili, Tajammul; Lurie, A.; Corey, Eva; Shi, Runhua; Yeh, Yunshin; Yu, Xiuping

doi:10.1038/s41391-020-0229-z

Cited by 35 publications

(36 citation statements)

References 32 publications

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“…However, the precise mechanism leading to PKD due to NEK1 insufficiency is not clear, but a clue came from the discovery that NEK1 interacts with and phosphorylates TAZ, involved in the E3 ligase complex, which regulates the stability of polycystin 2 [18]. TAZ is also a paralog of yes-associated protein (YAP), a transcriptional coactivator that mediates many functions in normal development and in disease pathology, such as cancer progression, including prostate cancer [19][20][21][22].…”

Section: Introductionmentioning

confidence: 99%

NEK1 Phosphorylation of YAP Promotes Its Stabilization and Transcriptional Output

Khalil

Ghosh

Singh

et al. 2020

Cancers

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Most prostate cancer (PCa) deaths result from progressive failure in standard androgen deprivation therapy (ADT), leading to metastatic castration-resistant PCa (mCRPC); however, the mechanism and key players leading to this are not fully understood. While studying the role of tousled-like kinase 1 (TLK1) and never in mitosis gene A (NIMA)-related kinase 1 (NEK1) in a DNA damage response (DDR)-mediated cell cycle arrest in LNCaP cells treated with bicalutamide, we uncovered that overexpression of wt-NEK1 resulted in a rapid conversion to androgen-independent (AI) growth, analogous to what has been observed when YAP1 is overexpressed. We now report that overexpression of wt-NEK1 results in accumulation of YAP1, suggesting the existence of a TLK1>NEK1>YAP1 axis that leads to adaptation to AI growth. Further, YAP1 is co-immunoprecipitated with NEK1. Importantly, NEK1 was able to phosphorylate YAP1 on six residues in vitro, which we believe are important for stabilization of the protein, possibly by increasing its interaction with transcriptional partners. In fact, knockout (KO) of NEK1 in NT1 PCa cells resulted in a parallel decrease of YAP1 level and reduced expression of typical YAP-regulated target genes. In terms of cancer potential implications, the expression of NEK1 and YAP1 proteins was found to be increased and correlated in several cancers. These include PCa stages according to Gleason score, head and neck squamous cell carcinoma, and glioblastoma, suggesting that this co-regulation is imparted by increased YAP1 stability when NEK1 is overexpressed or activated by TLK1, and not through transcriptional co-expression. We propose that the TLK1>NEK1>YAP1 axis is a key determinant for cancer progression, particularly during the process of androgen-sensitive to -independent conversion during progression to mCRPC.

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Section: Introductionmentioning

confidence: 99%

NEK1 Phosphorylation of YAP Promotes Its Stabilization and Transcriptional Output

Khalil

Ghosh

Singh

et al. 2020

Cancers

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“…However, the loss of TAZ expression has been reported in PC and it has been proposed that when TAZ is re-expressed, it results in a more aggressive disease. Contrary to this, expression in NEPC is reported as reduced or lost [80]; therefore, further investigation is still required. In breast cancers, the deubiquitinase USP1 can interact with TAZ to cause increased protein stability [104].…”

Section: Taz/wwtr1mentioning

confidence: 78%

“…They found that YAP1 is localised to basal epithelial cells in normal prostate and its protein expression increased with grade in prostate adenocarcinoma. However, upon investigation of mRNA levels in NEPCs, expression of YAP1 appears to be reduced, whilst in 12 samples that were investigated for protein expression, 6 did not show expression, with the other 6 showing staining in less than 25% of cells [80]. Therefore, it would be useful to assess not only more samples to clarify any associations of YAP expression with the NEPC phenotype, but to also investigate both the protein and the transcript in the same samples to determine whether there is a discord between the two, particularly when protein stability appears to be a key regulating factor for YAP.…”

Section: Yap1mentioning

confidence: 98%

Targeting the Hippo Pathway in Prostate Cancer: What’s New?

Coffey

2021

Cancers

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Identifying novel therapeutic targets for the treatment of prostate cancer (PC) remains a key area of research. With the emergence of resistance to androgen receptor (AR)-targeting therapies, other signalling pathways which crosstalk with AR signalling are important. Over recent years, evidence has accumulated for targeting the Hippo signalling pathway. Discovered in Drosophila melanogasta, the Hippo pathway plays a role in the regulation of organ size, proliferation, migration and invasion. In response to a variety of stimuli, including cell–cell contact, nutrients and stress, a kinase cascade is activated, which includes STK4/3 and LATS1/2 to inhibit the effector proteins YAP and its paralogue TAZ. Transcription by their partner transcription factors is inhibited by modulation of YAP/TAZ cellular localisation and protein turnover. Trnascriptional enhanced associate domain (TEAD) transcription factors are their classical transcriptional partner but other transcription factors, including the AR, have been shown to be modulated by YAP/TAZ. In PC, this pathway can be dysregulated by a number of mechanisms, making it attractive for therapeutic intervention. This review looks at each component of the pathway with a focus on findings from the last year and discusses what knowledge can be applied to the field of PC.

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“…In addition, these basal cells characteristically express the transcription factors SOX2 ( Figure 1F ; ref. 14 ), YAP-1 ( 15 ) and nerve growth factor receptor (NGFR, also known as p75; Figure 1D ; ref. 16 ), coupled with low-to-moderate HOXB13 expression ( Figure 1G ; ref.…”

Section: Introductionmentioning

confidence: 99%

“…In the third lineage, progenitors differentiated into luminal cell progeny, which maintained the expression of KRT8 and KRT18 while losing the expression of all other stem/progenitor markers (i.e., KRT5, KRT6A, KRT14, KRT19, and p63, Figure 1D ; GSTP1, Figure 1E ; SOX2, Figure 1F ; YAP-1 and NFGR, Figure 1D ; refs. 6 – 11 , 15 ). In addition, they acquire the expression of AR ( 6 ) and prostate-specific membrane antigen (PSMA, also known as FOLH1; ref.…”

Section: Introductionmentioning

confidence: 99%

Resistance to androgen receptor signaling inhibition does not necessitate development of neuroendocrine prostate cancer

Brennen¹,

Zhu²,

Coleman³

et al. 2021

JCI Insight

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Resistance to AR signaling inhibitors (ARSis) in a subset of metastatic castration-resistant prostate cancers (mCRPCs) occurs with the emergence of AR – neuroendocrine prostate cancer (NEPC) coupled with mutations/deletions in PTEN , TP53 , and RB1 and the overexpression of DNMTs, EZH2, and/or SOX2. To resolve whether the lack of AR is the driving factor for the emergence of the NE phenotype, molecular, cell, and tumor biology analyses were performed on 23 xenografts derived from patients with PC, recapitulating the full spectrum of genetic alterations proposed to drive NE differentiation. Additionally, phenotypic response to CRISPR/Cas9-mediated AR KO in AR + CRPC cells was evaluated. These analyses document that (a) ARSi-resistant NEPC developed without androgen deprivation treatment; (b) ARS in ARSi-resistant AR + /NE + double-positive “amphicrine” mCRPCs did not suppress NE differentiation; (c) the lack of AR expression did not necessitate acquiring a NE phenotype, despite concomitant mutations/deletions in PTEN and TP53 , and the loss of RB1 but occurred via emergence of an AR – /NE – double-negative PC (DNPC); (d) despite DNPC cells having homogeneous genetic driver mutations, they were phenotypically heterogeneous, expressing basal lineage markers alone or in combination with luminal lineage markers; and (e) AR loss was associated with AR promoter hypermethylation in NEPCs but not in DNPCs.

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The expression of YAP1 is increased in high-grade prostatic adenocarcinoma but is reduced in neuroendocrine prostate cancer

Cited by 35 publications

References 32 publications

NEK1 Phosphorylation of YAP Promotes Its Stabilization and Transcriptional Output

NEK1 Phosphorylation of YAP Promotes Its Stabilization and Transcriptional Output

Targeting the Hippo Pathway in Prostate Cancer: What’s New?

Resistance to androgen receptor signaling inhibition does not necessitate development of neuroendocrine prostate cancer

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