Glycine decarboxylase activity drives non-small cell lung cancer tumor-initiating cells and tumorigenesis.
Identification of the factors critical to the tumor-initiating cell (TIC) state may open new avenues in cancer therapy. Here we show that the metabolic enzyme glycine decarboxylase (GLDC) is critical for TICs in non-small cell lung cancer (NSCLC). TICs from primary NSCLC tumors express high levels of the oncogenic stem cell factor LIN28B and GLDC, which are both required for TIC growth and tumorigenesis. Overexpression of GLDC and other glycine/serine enzymes, but not catalytically inactive GLDC, promotes cellular transformation and tumorigenesis. We found that GLDC induces dramatic changes in glycolysis and glycine/serine metabolism, leading to changes in pyrimidine metabolism to regulate cancer cell proliferation. In the clinic, aberrant activation of GLDC correlates with poorer survival in lung cancer patients, and aberrant GLDC expression is observed in multiple cancer types. This link between glycine metabolism and tumorigenesis may provide novel targets for advancing anticancer therapy.
Stem Cell and Developmental Biology, Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672.
Wen Cai
WC
Zhang
Ng
N
Shyh-Chang
He
H
Yang
Amit
A
Rai
Shivshankar
S
Umashankar
Siming
S
Ma
Boon Seng
BS
Soh
Li Li
LL
Sun
Bee Choo
BC
Tai
Min En
ME
Nga
Kishore Kumar
KK
Bhakoo
Senthil Raja
SR
Jayapal
Massimo
M
Nichane
Qiang
Q
Yu
Dokeu A
DA
Ahmed
Christie
C
Tan
Wong Poo
WP
Sing
John
J
Tam
Agasthian
A
Thirugananam
Monireh Soroush
MS
Noghabi
Yin Huei
YH
Pang
Haw Siang
HS
Ang
Wayne
W
Mitchell
Paul
P
Robson
Philipp
P
Kaldis
Ross Andrew
RA
Soo
Sanjay
S
Swarup
Elaine Hsuen
EH
Lim
Bing
B
Lim
D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D004268:DNA-Binding Proteins / Q000378:metabolism; D005326:Fetal Proteins / Q000378:metabolism; D005998:Glycine / Q000378:metabolism; D050841:Glycine Dehydrogenase (Decarboxylating) / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics; D016601:RNA-Binding Proteins; D016415:Sequence Alignment; D012694:Serine / Q000378:metabolism; D016963:Thermus thermophilus / Q000201:enzymology; D014183:Transplantation, Heterologous; D020410:Activated-Leukocyte Cell Adhesion Molecule
D015703:Antigens, CD; D015816:Cell Adhesion Molecules, Neuronal; D004268:DNA-Binding Proteins; D005326:Fetal Proteins; D005998:Glycine; D050841:Glycine Dehydrogenase (Decarboxylating); D016601:RNA-Binding Proteins; D012694:Serine; C105613:ALCAM protein, human; D020410:Activated-Leukocyte Cell Adhesion Molecule; C516326:LIN28B protein, human