Abstract
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-β1 (TGF-β1) 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-β1 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-β1-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.
Highlights
Cancer cells exert malignant phenotypes partially through reprogramming the posttranslational modification (PTM) patterns of cancer-relevant proteins in response to extracellular and intracellular stimuli [1]
O-GlcNAcylation is a novel PTM of MORC family CW-type zinc finger 2 (MORC2), which is required for breast cancer progression
We recently demonstrated that MORC2 undergoes signaling-dependent phosphorylation [31], acetylation [30], and poly(ADP-ribosyl)ation [32], and these PTMs are implicated in the resistance of breast cancer cells to endocrine therapy drugs and DNA-damaging therapeutic agents
Summary
Cancer cells exert malignant phenotypes partially through reprogramming the posttranslational modification (PTM) patterns of cancer-relevant proteins in response to extracellular and intracellular stimuli [1]. Treatment proteins have fundamental roles in cancer progression and of MCF-7 and T47D cells with glucose, which produces the donor therapeutic responsiveness through integrating the extracellular substrate UDP-GlcNAc for OGT through HBP [3], resulted in an and intracellular signals to control gene transcription and DNA increase in MORC2 O-GlcNAcylation in a dose-dependent manner damage response [17]. To genes connective tissue growth factor (CTGF) and snail family determine which residue is the major O-GlcNAcylation site in transcriptional repressor 1 (SNAIL) and is crucial for breast cancer MORC2, we individually mutated those five residues to alanine (A), progression These findings reveal novel mechanistic insights into which lacks the hydroxy group in the side chain and blocks. The indicated antibodies showed that mutation of T556, but not the other four residues, resulted in a decrease in MORC2
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