Epigenetic downregulation of the ISG15-conjugating enzyme UbcH8 impairs lipolysis and correlates with poor prognosis in nasopharyngeal carcinoma

// Xiaoying Zhou 1, 2, * , Jiazhang Wei 1, * , Fu Chen 3 , Xue Xiao 1 , Tingting Huang 1 , Qian He 1 , Shumin Wang 1 , Chunping Du 1 , Yingxi Mo 1, 4 , Longde Lin 5 , Ying Xie 1 , Lili Wei 1 , Ying Lan 1 , Mairiko Murata 4 , Guangwu Huang 1 , Ingemar Ernberg 2 , Liudmila Matskova 2 , Zhe Zhang 1 1 Department of Otolaryngology-Head & Neck Surgery, First Affiliated Hospital of Guangxi Medical University, Guangxi, China 2 Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Solna, Sweden 3 Department of Radiation Oncology, Eye Ear Nose & Throat Hospital of Fudan University, Shanghai, China 4 Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, Mie, Japan 5 School of Public Health, Guangxi Medical University, Guangxi, China * These authors have contributed equally to this work Correspondence to: Ingemar Ernberg e-mail: ingemar.ernberg@ki.se Zhe Zhang e-mail: zhangzhe@gxmu.edu.cn Keywords: UBE2L6, nasopharyngeal carcinoma, DNA methylation, tumor suppressor gene, ATGL Received: April 30, 2015 Accepted: August 20, 2015 Published: October 12, 2015 ABSTRACT 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.