O-GlcNAcylation of NF-kappaB Promotes Lung Metastasis of Cervical Cancer Cells via Upregulation of CXCR4 Expression
Akhtar Ali1,3, Sung Hwan Kim2,3, Min Jun Kim1,3, Mee Young Choi1 , Sang Soo Kang1 ,
Gyeong Jae Cho1 ,Yoon Sook Kim1 , Jun-Young Choi2 , and Wan Sung Choi1,*
1Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, 2Departments of Thoriac and Cardiovascular
Surgery, Gyeongsang National University, School of Medicine, Jinju 52727, Korea, 3These authors contributed equally
to this work.
*Correspondence: choiws@gnu.ac.kr
Received May 31, 2017; Revised May 21, 2017; Accepted June 5, 2017.; Published online July 6, 2017.
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C-X-C chemokine receptor 4 (CXCR4) stimulates cancer metastasis. NF-kappaB regulates CXCR4 expression in cancer cells, and O-GlcNAc modification of NF-kappaB promotes its transcriptional activity. Here, we determined whether CXCR4 expression is affected by O-GlcNAcylation of NF-kappaB in lung metastasis of cervical cancer. We found elevated levels of O-linked-Nactylglucosamine transferase (OGT) and O-GlcNAcylation in cervical cancer cells compared to those in non-malignant epithelial cells and detected increased expression of NF-kappaB p65 (p65) and CXCR4 in cervical cancer cells. Knockdown of OGT inhibited the O-GlcNAcylation of p65 and decreased CXCR4 expression levels in HeLa cells. Thiamet G treatment increased O-GlcNAcylated p65, which subsequently enhanced CXCR4 expression levels. Inhibition of O-GlcNAcylation by 6- Diazo-5-oxo-L-norleucine (DON) treatment decreased p65 activation, eventually inhibiting CXCR4 expression in HeLa cells. Lung tissues from mice engrafted with OGT-knockdown HeLa cells (shOGT) exhibited lower expression of Ki-67 and HPV E6 and E7 oncogenes compared to lung tissues from mice engrafted with control HeLa cells (shCTL). In addition, lung tissues from mice engrafted with shOGT cells exhibited lower p65 and CXCR4 immunoreactivity compared to tissues from mice engrafted with shCTL cells. Taken together, our data suggest that p65 O-GlcNAcylation promotes lung metastasis of cervical cancer cells by activating CXCR4 expression.
Keywords: cervical cancer, CXCR4, lung metastasis, NF-kappaB p65, O-GlcNAcylation

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30 June 2017 Volume 40,
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