Twist regulates Yorkie activity to guide lineage reprogramming of syncytial alary muscles

Rose, Marcel; Domsch, Katrin; Bartle-Schultheis, Jakob; Reim, Ingolf; Schaub, Christoph

doi:10.1016/j.celrep.2022.110295

Cited by 4 publications

(6 citation statements)

References 62 publications

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“…When we analyzed the YAP/TEAD-dependent transcripts, we confirmed that in the YAP-expressing cells, Zeb1 and Twist1 (referred as Twist), two key transcriptional repressors of E-cadherin and downstream targets of YAP/TEAD, were oppositely regulated in the LNCaP-YAP 1-WT and Y407F-expressing cells. However, E-cadherin (E-CAD) was strongly reduced in the YAP1-WT cells, and also in the Y40F mutant ( Figure 4 ) possibly through a more complex reciprocal regulation by Twist and YAP1 [ 23 , 24 ]. In fact, the reciprocally regulated Twist target gene N-cadherin (N-CAD) was suppressed only in the Y407F-expressing cells.…”

Section: Resultsmentioning

confidence: 99%

NEK1-Mediated Phosphorylation of YAP1 Is Key to Prostate Cancer Progression

et al. 2023

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The key to preventing mCRPC progression is understanding how androgen-dependent PCa cells progress to independence and modify their transcriptional repertoire accordingly. We recently identified a novel axis of the Hippo pathway characterized by the sequential kinase cascade induced by androgen deprivation, AR−>TLK1B>NEK1>pYAP1-Y407, leading to CRPC adaptation. Phosphorylation of YAP1-Y407 increases upon ADT or induction of DNA damage, correlated with the known increase in NEK1 expression/activity, and this is suppressed in the Y407F mutant. Dominant expression of YAP1-Y407F in Hek293 cells reprograms the YAP1-mediated transcriptome to reduce TEAD- and p73-regulated gene expression and mediates sensitivity to MMC. NEK1 haploinsufficient TRAMP mice display reduced YAP1 expression and, if castrated, fail to progress to overt prostate carcinomas, even while displaying reduced E-Cadherin (E-Cad) expression in hyperplastic ductules. YAP1 overexpression, but not the Y407F mutant, transforms LNCaP cells to androgen-independent growth with a mesenchymal morphology. Immunohistochemical examination of prostate cancer biopsies revealed that the pYAP1-Y407 nuclear signal is low in samples of low-grade cancer but elevated in high GS specimens. We also found that J54, a pharmacological inhibitor of the TLK1>NEK1>YAP1 nexus leading to degradation of YAP1, can suppress the transcriptional reprogramming of LNCaP cells to androgen-independent growth and EMT progression, even when YAP1-WT is overexpressed.

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Section: Resultsmentioning

confidence: 99%

NEK1-Mediated Phosphorylation of YAP1 Is Key to Prostate Cancer Progression

et al. 2023

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“…However, E-Cadherin was strongly reduced in the wt-YAP cells, and also in the Y40F mutant (Fig. 4) possibly through a more complex reciprocal regulation by Twist and YAP [23] [24]. And in fact, the reciprocally regulated Twist target gene N-Cadherin was suppressed only in the Y407F expressing cells.…”

Section: Resultsmentioning

confidence: 99%

NEK1-Mediated Phosphorylation of YAP1 is key to Prostate Cancer Progression

Ghosh

Khalil

Mirza

et al. 2023

Preprint

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Standard therapy for advanced Prostate Cancer (PCa) consists of anti-androgens, which delays disease progression, but ultimately fails resulting in the incurable phase of the disease: Metastatic Castrate Resistant PCa (mCRPC). Targeting PCa cells before their progression to mCRPC would greatly improve the outcome. Understanding how Androgen-dependent PCa cells progress to independence and modify accordingly their transcriptional repertoire is the key to preventing mCRPC progression. We recently identified a novel axis of the Hippo pathway characterized by the sequential kinase cascade induced by androgen deprivation: AR down, leads to TLK1B up resulting in NEK1 activation which phosphorylates YAP1-Y407 leading to CRPC adaptation. We have now investigated additional details of this pathway with several different approaches. Firstly, we have overexpressed YAP1-WT or Y407F unphosphorylatable mutant in two cell lines (Hek293 and LNCaP) and have investigated their phenotypic and transcriptional changes, key among which was the adaptation of LNCaP cells expressing only the YAP1-WT to growth in androgen-depleted medium and progression to an EMT morphology, accompanied by transcriptional changes. Similarly, NT1 mouse PCa cells deficient in NEK1 displayed reduced motility concomitant with their reduced expression of N-Cadherin and Twist that we previously reported. Hek293 overexpressing YAP1-WT displayed greater induction of the apoptotic program in response to MMC, which is a feat dependent on the YAP1/p73 transcriptional programming, which further confirmed that YAP1-WT is significantly more stable and active as a co-activator than the Y407F mutant. Secondly, we investigated the importance of the NEK1>YAP1 axis in a GEMM generated by crossing TRAMP with NEK1-KO mice, and remarkably found that TRAMP mice haploinsufficient for NEK1 fail to progress to overt PRAD if castrated by 12 weeks. Finally, we have examined a collection of PCa biopsies by IHC using YAP1 and pYAP1-Y407 antisera and have found that the pYAP1- Y407 signal is low in samples of low-grade cancer but elevated in high gleason score (GS) specimens, whereas probing with the pan-YAP1 antiserum could not reveal this distinction so markedly. Importantly, we also found that J54, pharmacological inhibitor of the TLK1>NEK1>YAP1 nexus, leading to degradation of YAP1 can suppress the transcriptional reprogramming of LNCaP cells to Androgen-Independent (AI) growth and EMT progression even when YAP1-WT is overexpressed.

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“…Like AM FC specification, AM to VLM transdifferentiation is controlled by Org-1/Tbx1 and Tup/Islet1. It also requires Twi acting downstream of Org-1 ( Schaub et al, 2015 ; Rose et al, 2022 ). Further dissection of this naturally occurring transdifferentiation process will likely bring more information into mechanisms of cellular reprogramming during ontogeny and tissue regeneration.…”

Section: Trans-differentiation Of Ams At Metamorphosismentioning

confidence: 99%

“…More broadly, Tbx1 and Islet1 are major conserved actors in the genetic program controlling pharyngeal muscle development in chordates while Twi is involved in formation and regeneration of extraocular muscles ( Nathan et al, 2008 ; Sambasivan et al, 2011 ; Zhao et al, 2020 ; Whitman et al, 2022 ). In Drosophila, the Tbx1/Islet1 genetic hierarchy selectively controls AM/TARM development and, together with Twi, AM into VLM trans-differentiation ( Boukhatmi et al, 2014 ; Schaub et al, 2015 ; Rose et al, 2022 ). Whether the Tbx1/Islet1 hierarchy has been recruited during evolution for diversification and specific adaptations of striated muscles is an open question.…”

Section: Ancestral Origin and Evolution Of Ams; The Tbx1-islet1 (Twi)...mentioning

confidence: 99%

Insights and perspectives on the enigmatic alary muscles of arthropods

Bataillé,

Lebreton,

Boukhatmi

et al. 2024

Front. Cell Dev. Biol.

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Three types of muscles, cardiac, smooth and skeletal muscles are classically distinguished in eubilaterian animals. The skeletal, striated muscles are innervated multinucleated syncytia, which, together with bones and tendons, carry out voluntary and reflex body movements. Alary muscles (AMs) are another type of striated syncytial muscles, which connect the exoskeleton to the heart in adult arthropods and were proposed to control hemolymph flux. Developmental studies in Drosophila showed that larval AMs are specified in embryos under control of conserved myogenic transcription factors and interact with excretory, respiratory and hematopoietic tissues in addition to the heart. They also revealed the existence of thoracic AMs (TARMs) connecting to specific gut regions. Their asymmetric attachment sites, deformation properties in crawling larvae and ablation-induced phenotypes, suggest that AMs and TARMs could play both architectural and signalling functions. During metamorphosis, and heart remodelling, some AMs trans-differentiate into another type of muscles. Remaining critical questions include the enigmatic modes and roles of AM innervation, mechanical properties of AMs and TARMS and their evolutionary origin. The purpose of this review is to consolidate facts and hypotheses surrounding AMs/TARMs and underscore the need for further detailed investigation into these atypical muscles.

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Twist regulates Yorkie activity to guide lineage reprogramming of syncytial alary muscles

Abstract: Highlights d Twist mediates fate plasticity during transdifferentiation of syncytial muscle cells d Twist induces Yorkie activity to promote dedifferentiation and reprogramming d Twist/Yki/FGFR regulatory axis is required for lineage switch during reprogramming

Cited by 4 publications

References 62 publications

NEK1-Mediated Phosphorylation of YAP1 Is Key to Prostate Cancer Progression

NEK1-Mediated Phosphorylation of YAP1 Is Key to Prostate Cancer Progression

NEK1-Mediated Phosphorylation of YAP1 is key to Prostate Cancer Progression

Insights and perspectives on the enigmatic alary muscles of arthropods

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