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ABHD5 inhibits YAP-induced c-Met overexpression and colon cancer cell stemness via suppressing YAP methylation

ABSTRACT: Cancer stemness represents a major source of development and progression of colorectal cancer (CRC). c-Met critically contributes to CRC stemness, but how c-Met is activated in CRC remains elusive. We previously identified the lipolytic factor ABHD5 as an important tumour suppressor gene in CRC. Here, we show that loss of ABHD5 promotes c-Met activation to sustain CRC stemness in a non-canonical manner. Mechanistically, we demonstrate that ABHD5 interacts in the cytoplasm with the core subunit of the SET1A methyltransferase complex, DPY30, thereby inhibiting the nuclear translocation of DPY30 and activity of SET1A. In the absence of ABHD5, DPY30 translocates to the nucleus and supports SET1A-mediated methylation of YAP and histone H3, which sequesters YAP in the nucleus and increases chromatin accessibility to synergistically promote YAP-induced transcription of c-Met, thus promoting the stemness of CRC cells. This study reveals a novel role of ABHD5 in regulating histone/non-histone methylation and CRC stemness. We used microarrays to detail the gene expression of HCT116 colon cancer cell and ABHD5 knockdown HCT116 cell.

ORGANISM(S): Homo sapiens

PROVIDER: GSE185056 | GEO | 2021/11/24

REPOSITORIES: GEO

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ABHD5 inhibits YAP-induced c-Met overexpression and colon cancer cell stemness via suppressing YAP methylation

Project description:ABHD5 inhibits YAP-induced c-Met overexpression and colon cancer cell stemness via suppressing YAP methylation

| PRJNA767545 | ENA

SET1A-mediated mono-methylation at K342 regulates YAP activation by blocking its nuclear export and promotes tumorigenesis

Project description:YAP, a key effector of Hippo pathway, is activated by its translocation from cytoplasm to nucleus to regulate gene expression and promote tumorigenesis. Although the mechanism by which YAP is suppressed in cytoplasm has been well-studied, how the activated YAP is sequestered in the nucleus remains unknown. Here, we demonstrate that YAP is a nucleocytoplasmic shuttling protein and its nuclear export is controlled by SET1A-mediated mono-methylation of YAP at K342, which disrupts the binding of YAP to CRM1. YAP mimetic methylation knockin mice are more susceptible to colorectal tumorigenesis. Clinically, YAP K342 methylation is reversely correlated with cancer survival. Collectively, our study identifies SET1A mediated-mono-methylation at K342 as an essential regulatory mechanism for regulating YAP activity and tumorigenesis.

2018-05-23 | MSV000082392 | MassIVE

SET1A-mediated mono-methylation at K342 regulates YAP activation by blocking its nuclear export and promotes tumorigenesis

2018-05-23 | MSV000082393 | MassIVE

YAP and RUNX co-regulated genes in MCF10A

Project description:An antagonistic interplay between YAP and RUNX where RUNX proteins abrogate YAP-mediated transcription of EMT and Stemness associated genes in mammary epithelial cells in an interaction dependent manner.

2018-02-26 | GSE60876 | GEO

Function of YAP in glucose deprivation-induced gene expression

Project description:Knockdown of YAP in HCT116 cells by lentivirus-mediated shRNA, and after glucose deprivation treatment using total RNA for sequencing analysis to evaluate the function of YAP in glucose deprivation induced gene expression.

2023-11-29 | GSE215815 | GEO

Discovery of immediate YAP target genes with inducible form of YAP

Project description:Microarray analyses with cells/tissues overexpressing YAP have revealed many transcription targets of YAP (Dong et al, 2007; Zhao et al, 2008). However, as YAP induces transformation of non-cancerous cells, we thought many of known targets of YAP may be indirect consequence of transforming property of YAP. To identify the immediate transcription targets for YAP, we utilized immortalized mammary epithelial MCF-10A cells expressing a tamoxifen inducible, hyperactive (S127/381A) YAP mutant (MCF-10A ERT2-YAP 2SA). MCF-10A ERT2 and MCF-10A ERT2-YAP 2SA are generated. Each cell line was treated with 0.1% of ethanol (solvent) or 1uM of 4-hydroxytamoxifen for 2 or 6 hours. This makes 6 samples per set. The experiments were done in duplicate. The expression data from MCF-10A ERT2 and MCF-10A ERT2-YAP 2SA before tamoxifen treatment can serve as control.

2015-11-23 | E-GEOD-60579 | biostudies-arrayexpress

Transcription profiling by array of human MCF10A cells expressing YAP to identify the targets of the YAP oncogene

Project description:YAP is an oncogene and an inducer of Epithelial-to-Mesenchymal Transition (EMT). We used microarrays to detail the global program of gene expression to identify YAP target genes. PUBLICATION ABSTRACT:; The Hippo pathway defines a novel signaling cascade regulating cell proliferation and survival in Drosophila, which involves the negative regulation of the transcriptional coactivator Yorkie by the kinases Hippo and Warts. We have recently shown that the human ortholog of Yorkie, YAP, maps to a minimal amplification locus in mouse and human cancers, and that it mediates dramatic transforming activity in MCF10A primary mammary epithelial cells. Here we show that LATS proteins (mammalian orthologs of Warts) interact directly with YAP in mammalian cells and that ectopic expression of LATS1, but not LATS2, effectively suppresses the YAP phenotypes. Furthermore, shRNA-mediated knockdown of LATS1 phenocopies YAP overexpression. Since this effect can be suppressed by simultaneous YAP knockdown, it suggests that YAP is the primary target of LATS1 in mammalian cells. Expression profiling of genes induced by ectopic expression of YAP or by knockdown of LATS1 reveals a subset of potential Hippo pathway targets implicated in epithelial-to-mesenchymal transition (EMT), suggesting that this is a key feature of YAP signaling in mammalian cells. Experiment Overall Design: MCF10A cells were infected with retrovirus constructs (vector or YAP) and puromycin was used to select for transduced cells. Cells were split and grown to ~60-75%% confluency at which point they were harvested for RNA. Vector vs. YAP comparison was done in duplicate.

2008-06-11 | E-GEOD-10196 | biostudies-arrayexpress

c-Met regulation of tumor initiation and stemness occurs through CD44s

Project description:c-Met induces tumor initiation and stemness in HCC cells through the regulation of CD44s via AKT signaling. Over-expression of CD44s in c-Met and CD44s negative cells induce both a stemness and mesenchymal phenotype independent of c-Met. The down regulation of CD44s or c-Met was compared to Scrambled control to investigate the effects of CD44s or c-Met on global changes of mesenchymal or stemness markers.

2012-05-30 | E-GEOD-38343 | biostudies-arrayexpress

A systems approach to delineate functions of YAP family members

Project description:Duplication of genes encoding transcription factors plays an essential role in driving phenotypic variation. Because regulation can occur at multiple levels, it is often difficult to discern how each duplicated factor achieves its regulatory specificity. In these cases, a systems approach may distinguish the role of each factor by integrating complementary large-scale measurements of the regulatory network. To explore such an approach, we integrate growth phenotypes, promoter binding profiles, and gene expression patterns to model the DNA damage response network controlled by the Yeast-specific AP-1 (YAP) family of transcription factors. This analysis reveals that YAP regulatory specificity is achieved by at least three mechanisms: (a) Divergence of DNA-binding sequences into two subfamilies; (b) Condition-specific combinatorial regulation by multiple Yap factors; and (c) Interactions of Yap 1, 4, and 6 with chromatin remodeling proteins. Additional microarray experiments establish that Yap4 and 6 regulate gene expression through interactions with the histone deacetylase, Hda1. The data further highlight differences among Yap paralogs in terms of their regulatory mode of action (activation vs. repression). This study suggests how other large TF families might be disentangled in the future. Keywords: gene expression microarray and ChIP-chip Gene expression of wild type and single YAP deletion (YAP1/2/4/5/6) strains were profiled in media supplemented with either MMS or CDDP at two different concentrations. ChIP-chip of five YAPs (YAP1/2/4/6/6) were done in duplicate in both drug-treated (MMS or CDDP) or untreated (SC media) conditions.

2008-02-03 | E-GEOD-10146 | biostudies-arrayexpress

Effect of YAP overexpression on HuCCT1 cholangiocarcinoma cell line transcriptome (YAP overexpression)

Project description:The YAP pathway in regulating organ size by integrating external signals to control the expression of genes involved in cell proliferation. YAP is known to be involved in tumorigenesis in several tissues, yet its role in cholangiocarcinoma is not established We used microarrays to assess the role of YAP pathway in cholangiocarcinoma either by overexpressing a constitutively active YAP1 mutant, or by downregulating YAP1 expression using shRNA HuCCT1 cells where transfected with either an empty vector or a vector overexpressing the constitutively active YAP1 S127A; cells were harvested, RNA was collected and analyzed using microarray

2015-10-27 | E-GEOD-61764 | biostudies-arrayexpress

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