Cancer-Specific Production of N-Acetylaspartate via NAT8L Overexpression in Non-Small Cell Lung Cancer and Its Potential as a Circulating Biomarker.
In order to identify new cancer-associated metabolites that may be useful for early detection of lung cancer, we performed a global metabolite profiling of a non-small cell lung cancer (NSCLC) line and immortalized normal lung epithelial cells from the same patient. Among several metabolites with significant cancer/normal differences, we identified a unique metabolic compound, N-acetylaspartate (NAA), in cancer cells-undetectable in normal lung epithelium. NAA's cancer-specific detection was validated in additional cancer and control lung cells as well as selected NSCLC patient tumors and control tissues. NAA's cancer specificity was further supported in our analysis of NAA synthetase (gene symbol: NAT8L) gene expression levels in The Cancer Genome Atlas: elevated NAT8L expression in approximately 40% of adenocarcinoma and squamous cell carcinoma cases (N = 577), with minimal expression in all nonmalignant lung tissues (N = 74). We then showed that NAT8L is functionally involved in NAA production of NSCLC cells through siRNA-mediated suppression of NAT8L, which caused selective reduction of intracellular and secreted NAA. Our cell culture experiments also indicated that NAA biosynthesis in NSCLC cells depends on glutamine availability. For preliminary evaluation of NAA's clinical potential as a circulating biomarker, we developed a sensitive NAA blood assay and found that NAA blood levels were elevated in 46% of NSCLC patients (N = 13) in comparison with age-matched healthy controls (N = 21) among individuals aged 55 years or younger. Taken together, these results indicate that NAA is produced specifically in NSCLC tumors through NAT8L overexpression, and its extracellular secretion can be detected in blood. Cancer Prev Res; 9(1); 43-52. ©2015 AACR.
Department of Biological Sciences, University of Texas at Dallas, Richardson, Texas. Center for Systems Biology, University of Texas at Dallas, Richardson, Texas.
Tzu-Fang
TF
Lou
Center for Systems Biology, University of Texas at Dallas, Richardson, Texas. Department of Bioengineering, University of Texas at Dallas, Richardson, Texas.
Deepa
D
Sethuraman
Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas.
Patrick
P
Dospoy
Department of Biological Sciences, University of Texas at Dallas, Richardson, Texas. Center for Systems Biology, University of Texas at Dallas, Richardson, Texas.
Pallevi
P
Srivastva
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas.
Hyun Seok
HS
Kim
Department of Chemistry, University of Texas at Dallas, Richardson, Texas.
Joongsoo
J
Kim
Department of Biological Sciences, University of Texas at Dallas, Richardson, Texas.
Xiaotu
X
Ma
Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas.
Pei-Hsuan
PH
Chen
Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas.
Kenneth E
KE
Huffman
Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas.
Robin E
RE
Frink
Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas.
Jill E
JE
Larsen
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas. Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas.
Cheryl
C
Lewis
Division of Pulmonary and Critical Care Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Sang-Won
SW
Um
Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Seoul, Korea.
Duk-Hwan
DH
Kim
Department of Chemistry, University of Texas at Dallas, Richardson, Texas.
Jung-Mo
JM
Ahn
Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas. Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas.
Ralph J
RJ
DeBerardinis
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas. Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas.
Michael A
MA
White
Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas. Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas.
John D
JD
Minna
Department of Biological Sciences, University of Texas at Dallas, Richardson, Texas. Center for Systems Biology, University of Texas at Dallas, Richardson, Texas. Department of Bioengineering, University of Texas at Dallas, Richardson, Texas. hyuntae.yoo@utdallas.edu.
Hyuntae
H
Yoo
D000123:Acetyltransferases / Q000097:blood* / Q000378:metabolism; D000328:Adult; D000368:Aged; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000097:blood; D014408:Biomarkers, Tumor / Q000097:blood*; D001812:Blood-Brain Barrier; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000378:metabolism*; D016022:Case-Control Studies; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005973:Glutamine / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D034741:RNA, Small Interfering / Q000378:metabolism; D017423:Sequence Analysis, RNA
D014408:Biomarkers, Tumor; D034741:RNA, Small Interfering; D005973:Glutamine; D001224:Aspartic Acid; C000179:N-acetylaspartate; D000123:Acetyltransferases; C116373:NAT8 protein, human; C000611572:NAT8L protein, human