O-GlcNAcylation of MORC2 at threonine 556 by OGT couples TGF-β signaling to breast cancer progression

被引：60

作者：

Liu, Ying-Ying ^{[1
,2
,3
,4
,5
]}

Liu, Hong-Yi ^{[1
,2
]}

Yu, Tian-Jian ^{[1
,2
,3
,4
,5
]}

Lu, Qin ^{[1
,2
]}

Zhang, Fang-Lin ^{[1
,2
,3
,4
]}

Liu, Guang-Yu ^{[5
]}

Shao, Zhi-Ming ^{[1
,2
,3
,4
,5
,6
]}

Li, Da-Qiang ^{[1
,2
,3
,4
,5
,6
,7
]}

机构：

[1] Fudan Univ, Shanghai Canc Ctr, Inst Biomed Sci, Int Colab Med Epigenet & Metab,Minist Sci & Techn, Shanghai 200032, Peoples R China

[2] Fudan Univ, Inst Biomed Sci, Shanghai Key Lab Med Epigenet, Int Colab Med Epigenet & Metab,Minist Sci & Techn, Shanghai 200032, Peoples R China

[3] Fudan Univ, Shanghai Med Coll, Canc Inst, Shanghai 200032, Peoples R China

[4] Fudan Univ, Shanghai Med Coll, Dept Oncol, Shanghai 200032, Peoples R China

[5] Fudan Univ, Shanghai Med Coll, Dept Breast Surg, Shanghai 200032, Peoples R China

[6] Fudan Univ, Shanghai Med Coll, Shanghai Key Lab Breast Canc, Shanghai 200032, Peoples R China

[7] Fudan Univ, Shanghai Med Coll, Shanghai Key Lab Radiat Oncol, Shanghai 200032, Peoples R China

来源：

CELL DEATH AND DIFFERENTIATION | 2022年 / 29卷 / 04期

基金：

中国国家自然科学基金; 国家重点研发计划;

关键词：

TISSUE GROWTH-FACTOR; MARIE-TOOTH DISEASE; HUMAN GLUTAMINE-FRUCTOSE-6-PHOSPHATE AMIDOTRANSFERASE; TRANSCRIPTION FACTOR SNAIL; MESENCHYMAL TRANSITION; HIGH EXPRESSION; PROTEIN-KINASE; PHOSPHORYLATION; CELLS; METASTASIS;

D O I：

10.1038/s41418-021-00901-0

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

MORC family CW-type zinc finger 2 (MORC2) is a newly identified chromatin-remodeling enzyme involved in DNA damage response and gene transcription, and its dysregulation has been linked with Charcot-Marie-Tooth disease, neurodevelopmental disorder, and cancer. Despite its functional importance, how MORC2 is regulated remains enigmatic. Here, we report that MORC2 is O-GlcNAcylated by O-GlcNAc transferase (OGT) at threonine 556. Mutation of this site or pharmacological inhibition of OGT impairs MORC2-mediated breast cancer cell migration and invasion in vitro and lung colonization in vivo. Moreover, transforming growth factor-beta 1 (TGF-beta 1) induces MORC2 O-GlcNAcylation through enhancing the stability of glutamine-fructose-6-phosphate aminotransferase (GFAT), the rate-limiting enzyme for producing the sugar donor for OGT. O-GlcNAcylated MORC2 is required for transcriptional activation of TGF-beta 1 target genes connective tissue growth factor (CTGF) and snail family transcriptional repressor 1 (SNAIL). In support of these observations, knockdown of GFAT, SNAIL or CTGF compromises TGF-beta 1-induced, MORC2 O-GlcNAcylation-mediated breast cancer cell migration and invasion. Clinically, high expression of OGT, MORC2, SNAIL, and CTGF in breast tumors is associated with poor patient prognosis. Collectively, these findings uncover a previously unrecognized mechanistic role for MORC2 O-GlcNAcylation in breast cancer progression and provide evidence for targeting MORC2-dependent breast cancer through blocking its O-GlcNAcylation.

引用

页码：861 / 873

页数：13

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