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

Xiaoying Zhou; Jiazhang Wei; Fu Chen; Xue Xiao; Tingting Huang; Qian He; Shumin Wang; Chunping Du; Yingxi Mo; Longde Lin; Ying Xie; Lili Wei; Ying Lan; Mairiko Murata; Guangwu Huang; Ingemar Ernberg; Liudmila Matskova; Zhe Zhang

doi:10.18632/oncotarget.6218

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

Oncotarget. 2015 Dec 1;6(38):41077-91. doi: 10.18632/oncotarget.6218.

Authors

Xiaoying Zhou^{1

2}, Jiazhang Wei¹, Fu Chen³, Xue Xiao¹, Tingting Huang¹, Qian He¹, Shumin Wang¹, Chunping Du¹, Yingxi Mo^{1

4}, Longde Lin⁵, Ying Xie¹, Lili Wei¹, Ying Lan¹, Mairiko Murata⁴, Guangwu Huang¹, Ingemar Ernberg², Liudmila Matskova², Zhe Zhang¹

Affiliations

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.

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.

Keywords: ATGL; DNA methylation; UBE2L6; nasopharyngeal carcinoma; tumor suppressor gene.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Triphosphatases / genetics
Adenosine Triphosphatases / metabolism
Apoptosis / genetics
Azacitidine / analogs & derivatives
Azacitidine / pharmacology
Blotting, Western
Cell Cycle Proteins / genetics
Cell Cycle Proteins / metabolism
Cell Line, Tumor
Cell Proliferation / genetics
Cytokines / genetics
Cytokines / metabolism
DNA Methylation
Decitabine
Down-Regulation*
Enzyme Inhibitors / pharmacology
Epigenesis, Genetic*
Gene Expression Profiling / methods
Gene Expression Regulation, Neoplastic / drug effects
HEK293 Cells
Humans
Kaplan-Meier Estimate
Lipase / genetics
Lipase / metabolism
Lipid Droplets / metabolism
Lipolysis / genetics*
Nasopharyngeal Neoplasms / genetics*
Nasopharyngeal Neoplasms / metabolism
Nasopharyngeal Neoplasms / pathology
Prognosis
Promoter Regions, Genetic
RNA Interference
Reverse Transcriptase Polymerase Chain Reaction
Ubiquitin-Conjugating Enzymes / genetics*
Ubiquitin-Conjugating Enzymes / metabolism
Ubiquitins / genetics
Ubiquitins / metabolism
Valosin Containing Protein

Substances

Cell Cycle Proteins
Cytokines
Enzyme Inhibitors
Ubiquitins
ISG15 protein, human
Decitabine
UBE2L6 protein, human
Ubiquitin-Conjugating Enzymes
Lipase
PNPLA2 protein, human
Adenosine Triphosphatases
VCP protein, human
Valosin Containing Protein
Azacitidine