Epigenetic downregulation of the ISG15–conjugating enzyme UbcH8 impairs lipolysis and correlates with poor prognosis in nasopharyngeal carcinoma
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Xiaoying Zhou1,2,*, Jiazhang Wei1,*, Fu Chen3, Xue Xiao1, Tingting Huang1, Qian He1, Shumin Wang1, Chunping Du1, Yingxi Mo1,4, Longde Lin5, Ying Xie1, Lili Wei1, Ying Lan1, Mairiko Murata4, Guangwu Huang1, Ingemar Ernberg2, Liudmila Matskova2, Zhe Zhang1
1Department of Otolaryngology-Head & Neck Surgery, First Affiliated Hospital of Guangxi Medical University, Guangxi, China
2Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Solna, Sweden
3Department of Radiation Oncology, Eye Ear Nose & Throat Hospital of Fudan University, Shanghai, China
4Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, Mie, Japan
5School of Public Health, Guangxi Medical University, Guangxi, China
*These authors have contributed equally to this work
Ingemar Ernberg e-mail: email@example.com
Zhe Zhang e-mail: firstname.lastname@example.org
Keywords: UBE2L6, nasopharyngeal carcinoma, DNA methylation, tumor suppressor gene, ATGL
Received: April 30, 2015 Accepted: August 20, 2015 Published: October 12, 2015
We identified the UBE2L6 gene, encoding the ISG15-conjugating enzyme UbcH8, as one gene significantly downregulated by promoter hypermethylation in nasopharyngeal carcinoma (NPC). Reduced expression of the UbcH8 protein correlated with poor outcome in NPC patients. Restored expression of UBE2L6 suppressed proliferation and colony formation in NPC cells, while inducing apoptosis. Of particular interest, we found that aberrant lipid turnover was controlled by UbcH8 in NPC through ISG15-conjugation of valosin-containing protein (VCP). Tumor tissue and NPC cell lines showed conspicuously strong accumulation of lipid droplets (LDs) compared to control nasopharyngeal epithelium and non-cancerous cell lines. We demonstrated that UbcH8 counteracts degradation of adipocyte triglyceride lipase (ATGL), a key enzyme in lipid catabolism.
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