Abstract
O-GlcNAcylation is a post-translational modification that regulates a broad range of nuclear and cytoplasmic proteins and is emerging as a key regulator of various biological processes. Previous studies have shown that increased levels of global O-GlcNAcylation and O-GlcNAc transferase (OGT) are linked to the incidence of metastasis in breast cancer patients, but the molecular basis behind this is not fully known. In this study, we have determined that the actin-binding protein cofilin is O-GlcNAcylated by OGT and mainly, if not completely, mediates OGT modulation of cell mobility. O-GlcNAcylation at Ser-108 of cofilin is required for its proper localization in invadopodia at the leading edge of breast cancer cells during three-dimensional cell invasion. Loss of O-GlcNAcylation of cofilin leads to destabilization of invadopodia and impairs cell invasion, although the actin-severing activity or lamellipodial localization is not affected. Our study provides insights into the mechanism of post-translational modification in fine-tuning the regulation of cofilin activity and suggests its important implications in cancer metastasis.
Highlights
O-GlcNAcylation plays important roles in breast cancer metastasis, but the underlying mechanism is not fully known
Cofilin is O-GlcNAcylated at Ser-108, which is required for its proper localization in invadopodia and is implicated in promoting breast cancer cell invasion
O-GlcNAcylation of Cofilin Promotes Breast Cancer Cell Mobility—It has recently been reported that increased levels of global GlcNAcylation and O-GlcNAc transferase (OGT) are closely linked to the metastasis occurrence of breast cancer [27], suggesting that O-GlcNAcylation may play an important role in modulating the proteins associated with cell mobility
Summary
O-GlcNAcylation plays important roles in breast cancer metastasis, but the underlying mechanism is not fully known. Results: Cofilin is O-GlcNAcylated at Ser-108, which is required for its proper localization in invadopodia and is implicated in promoting breast cancer cell invasion. O-GlcNAcylation at Ser-108 of cofilin is required for its proper localization in invadopodia at the leading edge of breast cancer cells during threedimensional cell invasion. Loss of O-GlcNAcylation of cofilin leads to destabilization of invadopodia and impairs cell invasion, the actin-severing activity or lamellipodial localization is not affected. Our study provides insights into the mechanism of post-translational modification in fine-tuning the regulation of cofilin activity and suggests its important implications in cancer metastasis. Phosphorylation at Ser-3, catalyzed by LIM and TES family kinases [18, 19], is known to play a fundamental role in regulating cofilin activity. Our findings provide insights into the regulatory mechanisms of cofilin function and reveal the implications of aberrant cofilin O-GlcNAcylation in cancer malignancies
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