GPCR-Hippo Signaling in Cancer DOI Creative Commons
Jiaqian Luo, Fa‐Xing Yu

Cells, Journal Year: 2019, Volume and Issue: 8(5), P. 426 - 426

Published: May 8, 2019

The Hippo signaling pathway is involved in tissue size regulation and tumorigenesis. Genetic deletion or aberrant expression of some genes lead to enhanced cell proliferation, tumorigenesis, cancer metastasis. Recently, multiple studies have identified a wide range upstream regulators the pathway, including mechanical cues ligands G protein-coupled receptors (GPCRs). Through activation related proteins possibly rearrangements actin cytoskeleton, GPCR can potently modulate phosphorylation states activity YAP TAZ, two homologous oncogenic transcriptional co-activators, major effectors pathway. Herein, we summarize network, regulation, functions GPCR-Hippo signaling, will also discuss potential anti-cancer therapies targeting GPCR-YAP signaling.

Language: Английский

Mechanical Stiffness Controls Dendritic Cell Metabolism and Function DOI Creative Commons
Mainak Chakraborty, Kevin Chu, Annie Shrestha

et al.

Cell Reports, Journal Year: 2021, Volume and Issue: 34(2), P. 108609 - 108609

Published: Jan. 1, 2021

Stiffness in the tissue microenvironment changes most diseases and immunological conditions, but its direct influence on immune system is poorly understood. Here, we show that static tension impacts cell function, maturation, metabolism. Bone-marrow-derived and/or splenic dendritic cells (DCs) grown vitro at physiological resting stiffness have reduced proliferation, activation, cytokine production compared with under higher stiffness, mimicking fibro-inflammatory disease. Consistently, DCs increased activation flux of major glucose metabolic pathways. In DC models autoimmune diabetes tumor immunotherapy, primes to elicit an adaptive response. Mechanistic workup identifies Hippo-signaling molecule, TAZ, as well Ca2+-related ion channels, including potentially PIEZO1, important effectors impacting metabolism function tension. Tension also directs phenotypes monocyte-derived humans. Thus, mechanical a critical environmental cue innate immunity.

Language: Английский

Citations

163
Cholesterol Stabilizes TAZ in Hepatocytes to Promote Experimental Non-alcoholic Steatohepatitis DOI Creative Commons
Xiaobo Wang, Bishuang Cai, Xiaoming Yang

et al.

Cell Metabolism, Journal Year: 2020, Volume and Issue: 31(5), P. 969 - 986.e7

Published: April 6, 2020

Language: Английский

Citations

160
The Hippo Pathway in Liver Homeostasis and Pathophysiology DOI
Jordan H. Driskill, Duojia Pan

Annual Review of Pathology Mechanisms of Disease, Journal Year: 2020, Volume and Issue: 16(1), P. 299 - 322

Published: Nov. 25, 2020

Studies of the regenerative capacity liver have converged on Hippo pathway, a serine/threonine kinase cascade discovered in Drosophila and conserved from unicellular organisms to mammals. Genetic studies mouse rat livers revealed that pathway is key regulator size, regeneration, development, metabolism, homeostasis perturbations can lead development common diseases, such as fatty disease cancer. In turn, pharmacological targeting may be utilized boost regeneration prevent progression diseases. We review current insights provided by into pathophysiology. Furthermore, we present path forward for future understand how newly identified components control physiology regulated liver.

Language: Английский

Citations

144
Hippo signalling in the liver: role in development, regeneration and disease DOI
Jacquelyn O. Russell, Fernando D. Camargo

Nature Reviews Gastroenterology & Hepatology, Journal Year: 2022, Volume and Issue: 19(5), P. 297 - 312

Published: Jan. 21, 2022

Language: Английский

Citations

127
The role of ubiquitination and deubiquitination in tumor invasion and metastasis DOI Creative Commons
Shuangze Han, Ruike Wang, Yangnan Zhang

et al.

International Journal of Biological Sciences, Journal Year: 2022, Volume and Issue: 18(6), P. 2292 - 2303

Published: Jan. 1, 2022

Ubiquitination is vital for multiple cellular processes via dynamic modulation of proteins related to cell growth, proliferation, and survival.Of the ubiquitination system components, E3 ubiquitin ligases deubiquitinases have most prominent roles in modulating tumor metastasis.This review will briefly summarize observations underlying mechanisms regulate metastasis.Further, we discuss relationship importance between components progression.

Language: Английский

Citations

116
YAP1 and its fusion proteins in cancer initiation, progression and therapeutic resistance DOI Creative Commons
Frank Szulzewsky, Eric C. Holland, Valeri Vasioukhin

et al.

Developmental Biology, Journal Year: 2021, Volume and Issue: 475, P. 205 - 221

Published: Jan. 10, 2021

YAP1 is a transcriptional co-activator whose activity controlled by the Hippo signaling pathway. In addition to important functions in normal tissue homeostasis and regeneration, has also prominent cancer initiation, aggressiveness, metastasis, therapy resistance. this review we are discussing molecular of its roles cancer, with focus on different mechanisms de-regulation human cancers, including inactivation upstream pathway tumor suppressors, regulation intersecting pathways, miRNAs, viral oncogenes. We new findings function biology recently identified family gene fusions, that constitute type activating mutation likely oncogenic drivers several subtypes cancers. Lastly, discuss strategies therapeutic inhibition functions.

Language: Английский

Citations

113
The N6-methyladenosine METTL3 regulates tumorigenesis and glycolysis by mediating m6A methylation of the tumor suppressor LATS1 in breast cancer DOI Creative Commons
Youqin Xu, Song Mu, Ziyang Hong

et al.

Journal of Experimental & Clinical Cancer Research, Journal Year: 2023, Volume and Issue: 42(1)

Published: Jan. 7, 2023

Posttranscriptional modification of tumor-associated factors plays a pivotal role in breast cancer progression. However, the underlying mechanism remains unknown. M6A modifications cells are dynamic and reversible have been found to impact tumor initiation progression through various mechanisms. In this study, we explored regulatory cell proliferation metabolism m6A methylation Hippo pathway. METHODS: A combination MeRIP-seq, RNA-seq metabolomics-seq was utilized reveal map tissues cells. We conducted RNA pull-down assays, RIP-qPCR, MeRIP-qPCR, stability analysis identify relationship between proteins LATS1 regulation The expression biological functions were confirmed vitro vivo. Furthermore, investigated phosphorylation levels localization YAP/TAZ that activity pathway affected by RESULTS: demonstrated an important glycolytic factor, LATS1. METTL3 identified as writer, with YTHDF2 reader protein mRNA, which positive promoting both tumorigenesis glycolysis cancer. High induced mRNA. sites mRNA reduced its stability. Knockout or increased suppressed activating pathway.In summary, discovered METTL3-LATS1-YTHDF2

Language: Английский

Citations

59
Scribble mis-localization induces adaptive resistance to KRAS G12C inhibitors through feedback activation of MAPK signaling mediated by YAP-induced MRAS DOI
Yuta Adachi, Ryo Kimura, Kentaro Hirade

et al.

Nature Cancer, Journal Year: 2023, Volume and Issue: 4(6), P. 829 - 843

Published: June 5, 2023

Language: Английский

Citations

48
Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRASG12C Inhibitor Efficacy DOI
Suman Mukhopadhyay, Hsin‐Yi Huang, Ziyan Lin

et al.

Cancer Research, Journal Year: 2023, Volume and Issue: 83(24), P. 4095 - 4111

Published: Sept. 20, 2023

Abstract Non–small lung cancers (NSCLC) frequently (∼30%) harbor KRAS driver mutations, half of which are KRASG12C. KRAS-mutant NSCLC with comutated STK11 and/or KEAP1 is particularly refractory to conventional, targeted, and immune therapy. Development KRASG12C inhibitors (G12Ci) provided a major therapeutic advance, but resistance still limits their efficacy. To identify genes whose deletion augments efficacy the G12Cis adagrasib (MRTX-849) or plus TNO155 (SHP2i), we performed genome-wide CRISPR/Cas9 screens on KRAS/STK11-mutant lines. Recurrent, potentially targetable, synthetic lethal (SL) were identified, including serine–threonine kinases, tRNA-modifying proteoglycan synthesis enzymes, YAP/TAZ/TEAD pathway components. Several SL confirmed by siRNA/shRNA experiments, was extensively validated in vitro mice. Mechanistic studies showed that G12Ci treatment induced gene expression RHO paralogs activators, increased RHOA activation, evoked ROCK-dependent nuclear translocation YAP. Mice patients acquired G12Ci- G12Ci/SHP2i-resistant tumors strong overlap pathways, arguing for relevance screen results. These findings provide landscape potential targets future combination strategies, some can be tested rapidly clinic. Significance: Identification using screening credentialing ability TEAD inhibition enhance provides roadmap strategies. See related commentary Johnson Haigis, p. 4005

Language: Английский

Citations

43
SIRT7 promotes Hippo/YAP activation and cancer cell proliferation in hepatocellular carcinoma via suppressing MST1 DOI Creative Commons

Yiying Gu,

Cong Ding,

Tingzi Yu

et al.

Cancer Science, Journal Year: 2024, Volume and Issue: 115(4), P. 1209 - 1223

Published: Jan. 30, 2024

Abstract Abnormal activation of the oncogene YAP in Hippo pathway is a major feature liver cancer and inactivation MST1/2 has been shown to be responsible for overactivation that led tumorigenesis. However, mechanisms underlying dysregulation remain poorly understood. RNA‐seq analysis genome (KEGG) enrichment were used identify genes pathways regulated by SIRT7. qRT‐PCR, ChIP, luciferase assay investigate transcriptional regulation. Mass spectrometry, co‐immunoprecipitation immunoprecipitation exam protein–protein interaction post‐transcriptional modification. A xenograft mouse model was confirm effect SIRT7 inhibitors on hepatocellular carcinoma (HCC) proliferation vivo. We found suppresses MST1 both regulation modification, which turn promotes nuclear localization cancer. Mechanistically, we revealed transcription binding promoter inducing H3K18 deacetylation its region. In addition, directly binds deacetylates MST1, primes acetylation‐dependent ubiquitination protein degradation. clinical samples, confirmed negative correlation between levels, high expression correlated with elevated localization. specific inhibitor 2800Z sufficiently inhibited HCC growth disrupting SIRT7/MST1/YAP axis. Our data thus previously undescribed function regulating further proved targeting might provide novel therapeutic options treatment

Language: Английский

Citations

16