Fudan University Shanghai Cancer Center and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
Cancer Institute, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
Cell Death Differ. 2022 Apr;29(4):861-873. doi: 10.1038/s41418-021-00901-0. Epub 2022 Jan 1.
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.
MORC 家族 CW 型锌指 2（MORC2）是一种新发现的参与 DNA 损伤反应和基因转录的染色质重塑酶，其功能失调与 Charcot-Marie-Tooth 病、神经发育障碍和癌症有关。尽管它具有重要的功能，但 MORC2 的调控机制仍不清楚。在这里，我们报告 MORC2 可被 O-连接的 N-乙酰葡糖胺转移酶（OGT）在苏氨酸 556 位进行 O-连接的 N-乙酰葡糖胺化。该位点的突变或 OGT 的药理学抑制会损害 MORC2 介导的体外乳腺癌细胞迁移和侵袭以及体内肺定植。此外，转化生长因子-β1（TGF-β1）通过增强限速酶谷氨酰胺-果糖-6-磷酸氨基转移酶（GFAT）的稳定性来诱导 MORC2 的 O-连接的 N-乙酰葡糖胺化，GFAT 是产生 OGT 糖供体的酶。O-连接的 N-乙酰葡糖胺化的 MORC2 是 TGF-β1 靶基因结缔组织生长因子（CTGF）和蜗牛家族转录抑制因子 1（SNAIL）转录激活所必需的。这些观察结果得到了支持，敲低 GFAT、SNAIL 或 CTGF 会损害 TGF-β1 诱导的、MORC2 O-连接的 N-乙酰葡糖胺化介导的乳腺癌细胞迁移和侵袭。临床上，乳腺癌肿瘤中 OGT、MORC2、SNAIL 和 CTGF 的高表达与患者预后不良有关。总的来说，这些发现揭示了 MORC2 O-连接的 N-乙酰葡糖胺化在乳腺癌进展中的一个以前未被认识的机制作用，并为通过阻断其 O-连接的 N-乙酰葡糖胺化来靶向依赖 MORC2 的乳腺癌提供了证据。
