Journal
CELL DEATH AND DIFFERENTIATION
Volume 29, Issue 4, Pages 861-873Publisher
SPRINGERNATURE
DOI: 10.1038/s41418-021-00901-0
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Funding
- National Natural Science Foundation of China [81772805, 81972461, 82173275]
- National Key R&D Program of China [2017YFC0908400, 2018YFE0201600]
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This study reveals the importance of MORC2 O-GlcNAcylation in breast cancer progression. MORC2 is O-GlcNAcylated by OGT at threonine 556, and this modification is required for its role in breast cancer cell migration and invasion. TGF-beta 1 induces MORC2 O-GlcNAcylation through enhancing the stability of GFAT, and O-GlcNAcylated MORC2 is necessary for the transcriptional activation of TGF-beta 1 target genes CTGF and SNAIL. These findings provide evidence for targeting MORC2-dependent breast cancer through blocking its O-GlcNAcylation.
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.
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