Epigenetic downregulation of the ISG15-conjugating enzyme UbcH8 impairs lipolysis and correlates with poor prognosis in nasopharyngeal carcinoma.
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.
Department of Otolaryngology-Head & Neck Surgery, First Affiliated Hospital of Guangxi Medical University, Guangxi, China.|Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Solna, Sweden.
Xiaoying
X
Zhou
Department of Otolaryngology-Head & Neck Surgery, First Affiliated Hospital of Guangxi Medical University, Guangxi, China.
Jiazhang
J
Wei
Department of Radiation Oncology, Eye Ear Nose & Throat Hospital of Fudan University, Shanghai, China.
Fu
F
Chen
Department of Otolaryngology-Head & Neck Surgery, First Affiliated Hospital of Guangxi Medical University, Guangxi, China.
Xue
X
Xiao
Department of Otolaryngology-Head & Neck Surgery, First Affiliated Hospital of Guangxi Medical University, Guangxi, China.
Tingting
T
Huang
Department of Otolaryngology-Head & Neck Surgery, First Affiliated Hospital of Guangxi Medical University, Guangxi, China.
Qian
Q
He
Department of Otolaryngology-Head & Neck Surgery, First Affiliated Hospital of Guangxi Medical University, Guangxi, China.
Shumin
S
Wang
Department of Otolaryngology-Head & Neck Surgery, First Affiliated Hospital of Guangxi Medical University, Guangxi, China.
Chunping
C
Du
Department of Otolaryngology-Head & Neck Surgery, First Affiliated Hospital of Guangxi Medical University, Guangxi, China.|Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, Mie, Japan.
Yingxi
Y
Mo
School of Public Health, Guangxi Medical University, Guangxi, China.
Longde
L
Lin
Department of Otolaryngology-Head & Neck Surgery, First Affiliated Hospital of Guangxi Medical University, Guangxi, China.
Ying
Y
Xie
Department of Otolaryngology-Head & Neck Surgery, First Affiliated Hospital of Guangxi Medical University, Guangxi, China.
Lili
L
Wei
Department of Otolaryngology-Head & Neck Surgery, First Affiliated Hospital of Guangxi Medical University, Guangxi, China.
Ying
Y
Lan
Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, Mie, Japan.
Mairiko
M
Murata
Department of Otolaryngology-Head & Neck Surgery, First Affiliated Hospital of Guangxi Medical University, Guangxi, China.
Guangwu
G
Huang
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Solna, Sweden.
Ingemar
I
Ernberg
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Solna, Sweden.
Liudmila
L
Matskova
Department of Otolaryngology-Head & Neck Surgery, First Affiliated Hospital of Guangxi Medical University, Guangxi, China.
Zhe
Z
Zhang
D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D000077209:Decitabine; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D053208:Kaplan-Meier Estimate; D008049:Lipase / Q000235:genetics / Q000378:metabolism; D066292:Lipid Droplets / Q000378:metabolism; D008066:Lipolysis / Q000235:genetics*; D009303:Nasopharyngeal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics* / Q000378:metabolism; D014452:Ubiquitins / Q000235:genetics / Q000378:metabolism; D000074405:Valosin Containing Protein; D000217:Acyltransferases
D000251:Adenosine Triphosphatases; D001374:Azacitidine; D018797:Cell Cycle Proteins; D016207:Cytokines; D000077209:Decitabine; D004791:Enzyme Inhibitors; D008049:Lipase; D044763:Ubiquitin-Conjugating Enzymes; D014452:Ubiquitins; D000074405:Valosin Containing Protein; C074034:ISG15 protein, human; C471622:UBE2L6 protein, human; C494794:PNPLA2 protein, human; D000217:Acyltransferases; C000614178:VCP protein, human
ATGL; DNA methylation; UBE2L6; nasopharyngeal carcinoma; tumor suppressor gene