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O‑GlcNAcylation mediates endometrial cancer progression by regulating the Hippo‑YAP pathway.

ABSTRACT: The incidence of endometrial cancer (EC) is rapidly increasing worldwide. The majority of endometrial cancers are diagnosed at an early stage and are associated with a good prognosis; however, patients with advanced‑stage EC have a poor prognosis and present with invasive metastasis. The mechanisms responsible for the invasion and metastasis of endometrial cancer remain unknown. Here, the present study aimed to examine the effects of O‑GlcNAcylation on the malignancy of EC and its association with Yes‑associated protein (YAP). It was found that the expression of O‑GlcNAc transferase (OGT) and O‑GlcNAcylation were increased in EC tissues; the decrease in O‑GlcNAcylation levels was found to lead to the decreased proliferation, migration and invasion of EC cells. Mass spectrometric analysis revealed that OGT knockdown reduced the O‑GlcNAcylation of YAP. Furthermore, it was found that the reduction in the O‑GlcNAcylation of YAP promoted its phosphorylation, which in turn inhibited the access of YAP to the nucleus and downstream target gene activation, demonstrating that the level of O‑GlcNAcylation affects the development of EC. On the whole, the findings of the present study indicate that YAP is a key molecule linking the O‑GlcNAcylation and Hippo pathways, which together regulate the progression of EC.

SUBMITTER: Zhai L

PROVIDER: S-EPMC10552701 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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<i>O</i>‑GlcNAcylation mediates endometrial cancer progression by regulating the Hippo‑YAP pathway.

Zhai Lianghao L Yang Xiaoshan X Dong Jian J Qian Luomeng L Gao Yunge Y Lv Yanhong Y Chen Ligang L Chen Biliang B Zhou Fuxing F

International journal of oncology 20230623 2

The incidence of endometrial cancer (EC) is rapidly increasing worldwide. The majority of endometrial cancers are diagnosed at an early stage and are associated with a good prognosis; however, patients with advanced‑stage EC have a poor prognosis and present with invasive metastasis. The mechanisms responsible for the invasion and metastasis of endometrial cancer remain unknown. Here, the present study aimed to examine the effects of <i>O</i>‑GlcNAcylation on the malignancy of EC and its associa ...[more]

PMID: 37350405

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Project description:BackgroundN6-methyladenosine (m6A) has been shown to participate in various essential biological processes by regulating the level of target genes. However, the function of m6A modification mediated by KIAA1429 [alias virus-like m6A methyltransferase-associated protein (VIRMA)] during the progression of diffuse large B-cell lymphoma (DLBCL) remains undefined.MethodsThe expression and clinical significance of KIAA1429 were verified by our clinical data. CRISPR/Cas9 mediated KIAA1429 deletion, and CRISPR/dCas9-VP64 for activating endogenous KIAA1429 was used to evaluate its biological function. RNA sequencing (RNA-seq), methylated RNA immunoprecipitation sequencing (MeRIP-seq), RNA immunoprecipitation (RIP) assays, luciferase activity assay, RNA stability experiments, and co-immunoprecipitation were performed to investigate the regulatory mechanism of KIAA1429 in DLBCL. Tumor xenograft models were established for in vivo experiments.ResultsDysregulated expression of m6A regulators was observed, and a novel predictive model based on m6A score was established in DLBCL. Additionally, elevated KIAA1429 expression was associated with poor prognosis of patients with DLBCL. Knockout of KIAA1429 repressed DLBCL cell proliferation, facilitated cell cycle arrest in the G2/M phase, induced apoptosis in vitro, and inhibited tumor growth in vivo. Furthermore, carbohydrate sulfotransferase 11 (CHST11) was identified as a downstream target of KIAA1429, which mediated m6A modification of CHST11 mRNA and then recruited YTHDF2 for reducing CHST11 stability and expression. Inhibition of CHST11 diminished MOB1B expression, resulting in inactivation of Hippo-YAP signaling, reprogramming the expression of Hippo target genes.ConclusionsOur results revealed a new mechanism by which the Hippo-YAP pathway in DLBCL is inactivated by KIAA1429/YTHDF2-coupled epitranscriptional repression of CHST11, highlighting the potential of KIAA1429 as a novel predictive biomarker and therapeutic target for DLBCL progression.

Dataset Information

O‑GlcNAcylation mediates endometrial cancer progression by regulating the Hippo‑YAP pathway.

Publications

<i>O</i>‑GlcNAcylation mediates endometrial cancer progression by regulating the Hippo‑YAP pathway.

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