FOXA1 O-GlcNAcylation-mediated Transcriptional Switch Governs Metastasis Capacity in Breast Cancer

Overview

Journal Sci Adv

Specialties Biology
Science

Date 2023 Aug 18

PMID 37595040

Authors

Yajie Liu

Kairan Yu

Xiaotian Kong

Keren Zhang

Lingyan Wang

Nana Zhang

Qiushi Chen

Mingshan Niu

Wenli Li

Xiaomin Zhong

Sijin Wu

Jianing Zhang

Yubo Liu

Affiliations

Soon will be listed here.

Abstract

FOXA1, a transcription factor involved in epigenetic reprogramming, is crucial for breast cancer progression. However, the mechanisms by which FOXA1 achieves its oncogenic functions remain elusive. Here, we demonstrate that the O-linked β--acetylglucosamine modification (O-GlcNAcylation) of FOXA1 promotes breast cancer metastasis by orchestrating the transcription of numerous metastasis regulators. O-GlcNAcylation at Thr, Ser, and Ser regulates the stability of FOXA1 and promotes its assembly with chromatin. O-GlcNAcylation shapes the FOXA1 interactome, especially triggering the recruitment of the transcriptional repressor methyl-CpG binding protein 2 and consequently stimulating FOXA1 chromatin-binding sites to switch to chromatin loci of adhesion-related genes, including and . Site-specific depletion of O-GlcNAcylation on FOXA1 affects the expression of various downstream genes and thus inhibits breast cancer proliferation and metastasis both in vitro and in vivo. Our data establish the importance of aberrant FOXA1 O-GlcNAcylation in breast cancer progression and indicate that targeting O-GlcNAcylation is a therapeutic strategy for metastatic breast cancer.

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