Hippo-Independent Regulation of Yki/Yap/Taz: A Non-canonical View

Yang

et al. 2021

Front. Cell Dev. Biol.

Sexual size dimorphism (SSD) is the difference in segments or body size between sexes prevalent in various species. Understanding the genetic architecture of SSD has remained a significant challenge owing to the complexity of growth mechanisms and the sexual influences among species. The Chinese tongue sole (Cynoglossus semilaevis), which exhibits a female-biased SSD and sex reversal from female to pseudomale, is an ideal model for exploring SSD mechanism at the molecular level. The present study aimed to integrate transcriptome and methylome analysis to unravel the genetic and epigenetic changes in female, male, and pseudomale C. semilaevis. The somatotropic and reproductive tissues (brain, liver, gonad, and muscle) transcriptomes were characterized by RNA-seq technology. Transcriptomic analysis unravelled numerous differentially expressed genes (DEGs) involved in cell growth and death-related pathways. The gonad and muscle methylomes were further employed for screening differentially methylated genes (DMGs). Relatively higher DNA methylation levels were observed in the male and pseudomale individuals. In detail, hypermethylation of the chromosome W was pronounced in the pseudomale group than in the female group. Furthermore, weighted gene co-expression network analysis showed that turquoise and brown modules positively and negatively correlated with the female-biased SSD, respectively. A combined analysis of the module genes and DMGs revealed the female-biased mRNA transcripts and hypomethylated levels in the upstream and downstream regions across the cell cycle-related genes. Moreover, the male and pseudomale-biased gene expression in the hippo signaling pathway were positively correlated with their hypermethylation levels in the gene body. These findings implied that the activation of the cell cycle and the inhibition of the hippo signaling pathway were implicated in C. semilaevis female-biased SSD. In addition, the dynamic expression pattern of the epigenetic regulatory factors, including dnmt1, dnmt3a, dnmt3b, and uhrf1, among the different sexes correspond with their distinct DNA methylation levels. Herein, we provide valuable clues for understanding female-biased SSD in C. semilaevis.

Section: Discussionmentioning

confidence: 99%

Integration of Transcriptome and Methylome Highlights the Roles of Cell Cycle and Hippo Signaling Pathway in Flatfish Sexual Size Dimorphism

Yang

et al. 2021

Front. Cell Dev. Biol.

“…It has been identified that O-GlcNAcylation at the Ser109 site ( 34 ) and Thr241 site ( 35 ) of YAP stabilized YAP by antagonizing its Hippo-dependent phosphorylation, which incurred high-glucose-induced liver tumorigenesis. Interaction between YAP and O-GlcNAcylation links glucose abundance to Hippo signaling activity and tumorigenesis ( 36 ). Besides, YAP upregulates enzymes in glycolysis ( 37 ), including some critical rate-limiting enzymes.…”

Section: Hippo-yap-regulated Tumor Survivalmentioning

confidence: 99%

A narrative review for the Hippo-YAP pathway in cancer survival and immunity: the Yin-Yang dynamics

Wang¹,

Zhu²

2022

Transl Cancer Res TCR

The Hippo-YAP pathway is fast becoming a key instrument in regulating cancers. Binary oppositions, also known as the Yin-Yang dynamics in Chinese, have emerged in its effects. Some oppositions are attributable to in vitro and in vivo experimental conditions, some are due to differences between cancers or species, some are derived from its inherent duality endowed by upstream and downstream signaling, and some are yet unresolved mysteries. However, as bewildering they are, few have been noticed and defined so far. In this review, we first look back on the Hippo pathway which was initially identified more than a decade ago. We then focus on tumor biology, especially some latest popular mechanisms that regulate tumor cell survival, such as ferroptosis, autophagy, and apoptosis. The third chapter is concerned with the findings of the relationship between the Hippo pathway and tumor immunity on the microenvironment in which tumor cells progress. In each of these main sections the contradictory points of the Hippo pathway are elucidated and thoroughly examined. On one hand, the Yin-Yang dynamics of the Hippo pathway brings about considerable challenges for current research; on the other hand, this work will generate fresh insight into it and offer opportunities for subsequent drug development for cancer and regenerative medicine.

“…Following activation and interaction with partner transcription factors, the cofactors YAP and TAZ are then rendered able to regulate apoptosis, motility, growth, and cell proliferation. We should keep in mind that transcriptional activity of Yap and Taz can be modulated via other signaling pathways, which are also “non-canonical” pathways (for a review, please see [ 112 , 227 ]).…”

Section: Hippo Signalingmentioning

confidence: 99%

Molecular Alterations in Malignant Pleural Mesothelioma: A Hope for Effective Treatment by Targeting YAP

et al. 2022

Malignant pleural mesothelioma is a rare and aggressive neoplasm, which has primarily been attributed to the exposure to asbestos fibers (83% of cases); yet, despite a ban of using asbestos in many countries, the incidence of malignant pleural mesothelioma failed to decline worldwide. While little progress has been made in malignant pleural mesothelioma diagnosis, bevacizumab at first, then followed by double immunotherapy (nivolumab plus ipilumumab), were all shown to improve survival in large phase III randomized trials. The morphological analysis of the histological subtyping remains the primary indicator for therapeutic decision making at an advanced disease stage, while a platinum-based chemotherapy regimen combined with pemetrexed, either with or without bevacizumab, is still the main treatment option. Consequently, malignant pleural mesothelioma still represents a significant health concern owing to poor median survival (12–18 months). Given this context, both diagnosis and therapy improvements require better knowledge of the molecular mechanisms underlying malignant pleural mesothelioma’s carcinogenesis and progression. Hence, the Hippo pathway in malignant pleural mesothelioma initiation and progression has recently received increasing attention, as the aberrant expression of its core components may be closely related to patient prognosis. The purpose of this review was to provide a critical analysis of our current knowledge on these topics, the main focus being on the available evidence concerning the role of each Hippo pathway’s member as a promising biomarker, enabling detection of the disease at earlier stages and thus improving prognosis.