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Cancer-Specific Production of N-Acetylaspartate via NAT8L Overexpression in Non-Small Cell Lung Cancer and Its Potential as a Circulating Biomarker

 Tzu-Fang Lou  ;  Deepa Sethuraman  ;  Patrick Dospoy  ;  Pallevi Srivastva  ;  Hyun Seok Kim  ;  Joongsoo Kim  ;  Xiaotu Ma  ;  Pei-Hsuan Chen  ;  Kenneth E. Huffman  ;  Robin E. Frink  ;  Jill E. Larsen  ;  Cheryl Lewis  ;  Sang-Won Um  ;  Duk-Hwan Kim  ;  Jung-Mo Ahn  ;  Ralph J. DeBerardinis  ;  Michael A. White  ;  John D. Minna  ;  Hyuntae Yoo 
 CANCER PREVENTION RESEARCH, Vol.9(1) : 43-52, 2016 
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Issue Date
Acetyltransferases/blood* ; Acetyltransferases/metabolism ; Adult ; Aged ; Aspartic Acid/analogs & derivatives* ; Aspartic Acid/blood ; Biomarkers, Tumor/blood* ; Blood-Brain Barrier ; Carcinoma, Non-Small-Cell Lung/blood ; Carcinoma, Non-Small-Cell Lung/metabolism* ; Case-Control Studies ; Female ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic* ; Glutamine/metabolism ; Humans ; Lung Neoplasms/blood ; Lung Neoplasms/metabolism* ; Male ; Middle Aged ; RNA, Small Interfering/metabolism ; Sequence Analysis, RNA
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.
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1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
Yonsei Authors
Kim, Hyun Seok(김현석) ORCID logo https://orcid.org/0000-0003-4498-8690
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