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

Sep 24, 2026

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The incidence of endometrial cancer is rapidly rising worldwide, and while early-stage disease often responds better, advanced-stage cases develop invasive metastasis with poor outcomes. This study investigated how O‑GlcNAcylation influences endometrial cancer malignancy and its link to the Yes‑associated protein (YAP) within the Hippo pathway. OGT and O‑GlcNAcylation increased in tumors; reduced O‑GlcNAcylation decreased cell proliferation, migration, and invasion. Mass spectrometry showed OGT knockdown lowered O‑GlcNAcylation of YAP, increasing YAP phosphorylation, limiting nuclear access and downstream gene activation, thus connecting O‑GlcNAc levels to disease progression.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages13

Reading Time33 min

AccessFree to download

Abstract

Introduction

Endometrial cancer background and need for mechanisms

Metabolic disorders and O‑GlcNAcylation

Hippo pathway and YAP involvement

Materials and methods

Cells and cell culture

INTERNATIONAL JOURNAL OF ONCOLOGY 63: 90, 2023 O‑GlcNAcylation mediates endometrial cancer progression by regulating the Hippo‑YAP pathway LIANGHAO ZHAI 1* , XIAOSHAN YANG2,3* , JIAN DONG 1* , LUOMENG QIAN4 , YUNGE GAO 1 , YANHONG LV 1 , LIGANG CHEN 1 , BILIANG CHEN 1 and FUXING ZHOU 1 1Department of Gynecology and Obstetrics, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi 710032; 2Stomatology Hospital, Southern Medical University, Guangzhou, Guangdong 510280; 3State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, Air Force Medical University, Xi'an, Shaanxi 710032; 4Department of Medicine, Nankai University, Tianjin 300071, P.R. China Received December 8, 2022; Accepted May 24, 2023 DOI: 10.3892/ijo.2023.5538 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 YAPis a key molecule linking the O‑GlcNAcylation and Hippo pathways, which together regulate the progression of EC. Correspondence to: Dr Fuxing Zhou or Dr Biliang Chen, Department of Gynecology and Obstetrics, Xijing Hospital, Air Force Medical University, 127 Changle West Road, Xincheng, Xi'an, Shaanxi 710032, P.R. China E‑mail: [zhoufuxing1234@126.com](zhoufuxing1234@126.com) E‑mail: [cblxjh@fmmu.edu.cn](cblxjh@fmmu.edu.cn) *Contributed equally Key words: O‑GlcNAc, O‑GlcNAc transferase, endometrial cancer, Yes‑associated protein Introduction Endometrial cancer (EC), a common, malignant tumor presenting in young individuals, has a high invasiveness and low differentiation, and has become a major threat to the health of women worldwide (1,2) . Despite early diagnostic and therapeutic developments in recent years, patients with late‑stage EC still have a poor prognosis and exhibit aggressive metastases (3) . Hence, in order to determine effective inter‑ vention strategies for EC, the exploration of the mechanisms underlying its occurrence and development is critical. Metabolic disorders, such as diabetes, are a major risk factor for EC progression (4) . Hyperglycemia leads to an increase in the activity of the hexosamine biosynthesis pathway to promote O‑GlcNAcylation, which is a neces‑ sary post‑translational modification (PTM) (5,6) . The entire process is both reversible and dynamic, and is driven by O‑GlcNAc transferase (OGT) and inverted by O‑GlcNAcase (OGA) (7) . O‑GlcNAcylation is involved in numerous key cellular behaviors, such as translation, metabolism and apoptosis, with the potential to alter protein function either indirectly or directly in concert with phosphorylation (8,9) . The dysregulation of O‑GlcNAc metabolism has been linked to a variety of diseases, including diabetes, cancer and inflammation (10‑1

FAQs

What role does O‑GlcNAcylation play in endometrial cancer progression?

O‑GlcNAc transferase (OGT) and O‑GlcNAcylation levels were higher in endometrial cancer tissues. Reducing O‑GlcNAcylation decreased endometrial cancer cell proliferation, migration, and invasion.

How are OGT and YAP connected in this study?

Mass spectrometry showed that OGT knockdown reduced the O‑GlcNAcylation of YAP. This reduction promoted YAP phosphorylation and reduced YAP nuclear activity.

How does altered YAP signaling affect Hippo pathway downstream gene activation?

Lower YAP O‑GlcNAcylation increased phosphorylation, which inhibited YAP access to the nucleus and suppressed downstream target gene activation. This supports a model where O‑GlcNAcylation regulates Hippo‑YAP signaling to influence endometrial cancer progression.

Sep 24, 2026

Uploaded by Stanford