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

ABSTRACT: 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.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Ping Wang

PROVIDER: MSV000082393 | MassIVE | Wed May 23 21:43:00 BST 2018

SECONDARY ACCESSION(S): PXD009872

REPOSITORIES: MassIVE

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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

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

Project description: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.

2021-11-24 | GSE185056 | GEO

Hippo pathway induces PIEZO1 expression to promote oral squamous cell carcinoma cell proliferation

Project description:Most cancer cells are exposed to extracellular environments, such as extracellular matrix, which commonly becomes stiffer along with transformation. It is conceivable that tumorous extracellular environments would be changing to affect tumor cell behavior. It has been reported that Hippo pathway responds to the extracellular environments and induces the nuclear localization of transcription activator, yes-associated protein (YAP), resulting in stimulating cell proliferation. Its pathway also regulates gene expression, but the precise molecule to meditate cell proliferating effect of Hippo pathway in oral squamous cell carcinoma (OSCC) is not well understood. Here, we examined the effects of YAP-mediated Hippo pathway in OSCC tumorigenesis. Loss-of-function experiments using siRNA or an inhibitor, and immunohistochemical analyses of tissue specimens obtained from OSCC specimens demonstrated that YAP-mediated Hippo pathway was involved in OSCC cell proliferation. We identified Piezo-type mechanosensitive ion channel component 1 (PIEZO1), a Ca2+ channel, as a downstream molecule of Hippo pathway and showed that elevated PIEZO1 expression was required for PIEZO1 agonist-dependent Ca2+ entry and cell proliferation in OSCC cells. Furthermore, the experiments using three-dimensional culture and suspension culture revealed that PIEZO1, of which expression was regulated by YAP-mediated Hippo pathway, was involved in OSCC cellular growth. Immunohistochemically, YAP overexpression with nucleus and/or cytoplasm was detected with both PIEZO1 and Ki-67 expression at high frequencies in tumor lesion, but not in non-tumor region, of OSCC specimens. These results suggest that the YAP-mediated Hippo/PIEZO1 axis, which might be activated by the tumorous extracellular environments, promotes OSCC tumor cell growth.

2020-05-08 | GSE150044 | GEO

A splicing switch of TEAD4 regulates Hippo-YAP signaling pathway to inhibit tumor proliferation

Project description:Splicing dysregulations extensively occur in cancers, yet the biological consequences of such alterations are mostly undefined. Here we report that the Hippo-YAP signaling, a key pathway that regulates cell proliferation and organ size, is under control of a new splicing switch. We show that TEAD4, the transcription factor that mediates Hippo-YAP signaling, undergoes alternative splicing facilitated by the tumor suppressor RBM4, producing a truncated isoform, TEAD4-S, which lacks N-terminal DNA-binding domain but maintains YAP-interaction domain. TEAD4-S is located in both nucleus and cytoplasm, acting as a dominant negative isoform to YAP activity. Consistently, TEAD4-S is reduced in cancer cells, and its re-expression suppresses cancer cell proliferation and migration, inhibiting tumor growth in xenograft mouse model. Furthermore, TEAD4-S is reduced in human cancers, and patients with elevated TEAD4-S levels have improved survival. Altogether these data reveal a novel RBM4-mediated splicing switch that serves to fine-tune Hippo-YAP pathway. Cell lines stably expressing YAP, YAP/TEAD4-S, YAP/TEAD4-FL, YAP/RBM4 and control vector were created, and the total RNA was purified from the cells using TRIzol reagents. The polyadenylated RNAs were purified for construction of sequencing library using kapa TruSeq Total RNA Sample Prep kits (UNC High Throughput Sequencing Facility).

2016-06-16 | E-GEOD-80372 | biostudies-arrayexpress

ROS-induced cytosolic release of mitochondrial PGAM5 accelerates colorectal cancer progression via MST3-mediated YAP activation

Project description:Aberrant mtROS release in response to mitochondrial stress are considered to be a major novel feature of neoplastic transformation. However, the molecular mechanisms by which mtROS contribute to CRC development have not been fully elucidated. In this study, we showed that upon sensing the mtROS signal, the mitochondrially localized phosphatase PGAM5 undergoes cleavage in the mitochondrial transmembrane domain, and then the Cleaved PGAM5 is released into the cytoplasm. Subsequently, Cleaved PGAM5 binds to the kinase MST3 in the cytoplasm to promote MST3 dephosphorylation, resulting in a decrease in MST3 activity. Importantly, MST3 inactivation failed to regulate YAP phosphorylation, leading to YAP translocation into the nucleus, consequently promoting CRC proliferation and metastasis. Collectively, our findings identified the PGAM5-MST3-YAP axis as an important molecular mechanism through which mtROS promotes CRC development.

2024-11-05 | GSE249865 | GEO

ROS-induced cytosolic release of PGAM5 accelerates cancer progression via MST3-YAP axis

2024-11-05 | GSE248431 | GEO

YAP induces an oncogenic transcriptional program through TET1-mediated epigenetic remodeling in liver growth and tumorigenesis

Project description:Epigenetic remodeling is essential for oncogene-induced cellular transformation and malignancy. In contrast to histone posttranslational modification, how oncogenic signaling remodels DNA methylation remains poorly understood. The oncoprotein YAP, a coactivator of the TEAD transcription factors mediating Hippo signaling, is widely activated in human cancer. Here we identify the 5-methylcytosine dioxygenase TET1 as a direct YAP target and a master regulator that coordinates the genome-wide epigenetic and transcriptional reprogramming of YAP target genes in the liver. YAP activation induces the expression of TET1, which physically interacts with TEAD to cause regional DNA demethylation, histone H3K27 acetylation and chromatin opening in YAP target genes to facilitate transcriptional activation. Loss of TET1 not only reverses YAP-induced epigenetic and transcriptional changes but also suppresses YAP-induced hepatomegaly and tumorigenesis. These findings exemplify how oncogenic signaling regulates site specificity of DNA demethylation to promote tumorigenesis and implicate TET1 as a potential target for modulating YAP signaling in physiology and diseases.

2022-05-09 | GSE178227 | GEO

ADAR1 controls apoptosis of stressed cells by inhibiting Staufen-mediated mRNA decay

Project description:Both p150 and p110 isoforms of ADAR1 convert adenosine to inosine in double-stranded RNA (dsRNA). The p150 isoform suppresses the dsRNA sensing mechanism that activates the interferon induction mediated by the MDA5-MAVS signaling. In contrast, the biological function of the p110 isoform localized in the nucleus remains largely unknown. Here we show that stress-activated phosphorylation of ADAR1p110 by MKK6/p38 MAP kinases promotes its binding to Exportin-5 and nuclear export to the cytoplasm. Once translocated to the cytoplasmic, ADAR1p110 suppresses apoptosis of stressed cells by protecting many anti-apoptotic gene transcripts that contain 3’UTR dsRNA structures such as those consisting of inverted Alu repeats. ADAR1p110 competitively inhibits binding of Staufen1 to the 3’UTR dsRNAs and antagonizes the Staufen1-mediated mRNA decay mechanism. Our studies revealed a new stress response mechanism regulated by MAP kinases, in which ADAR1p110 translocates to the cytoplasm and regulates a class of mRNAs required for survival of stressed cells.

2017-03-21 | GSE85455 | GEO

A splicing switch of TEAD4 regulates Hippo-YAP signaling pathway to inhibit tumor proliferation

2016-06-16 | GSE80372 | GEO

METTL3 preferentially enhances non-m6A translation of epigenetic factors and promotes tumorigenesis (meRIP, RIP and polysome-seq)

Project description:Methyltransferase-like 3 (METTL3) is the best known m6A methyltransferase of the N6-adenosine-methyltransferase complex that functions in the reversible epi-transcriptome modulation of m6A modification. Besides acting as a m6A methyltransferase, METTL3 also regulates mRNA translation as well as other biological processes either through m6A “reader”-mediated downstream effect or directly binding to m6A sites, but the underlying mechanism and biological significance of these cytoplasmic events remain undefined. Here, we demonstrated that METTL3 inhibition significantly delayed gastric tumorigenesis in patient-derived xenograft model. Intriguingly, global METTL3-binding profiling revealed METTL3 occupied numerous oncogenic mRNAs without m6A signals, indicating a novel mechanism independent of m6A machinery. Furthermore, METTL3 was observed to translocate from nucleus to cytoplasm during gastric carcinogenesis, and its cytoplasm-to-nucleus ratio was correlated with cancer progression. In addition, the nuclear retention of METTL3 nearly abolished its tumor-promoting activity. Mechanistically, METTL3 interacted with PABPC1 to promote RNA looping, thus facilitating the translation of multiple oncogenic mRNAs. Taken together, our findings indicate an unexpected role of METTL3 as an important translational regulator independent of either m6A-“writer” or -“reader” activities and suggest METTL3 as a therapeutic target in gastric cancer.

2022-05-16 | GSE163310 | GEO

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