title: Integrated analysis of transcriptomes of cancer cell lines and patient samples reveals STK11/LKB1-driven regulation of cAMP phosphodiesterase-4D.
abstract: The recent proliferation of data on large collections of well-characterized cancer cell lines linked to therapeutic drug responses has made it possible to identify lineage- and mutation-specific transcriptional markers that can help optimize implementation of anticancer agents. Here, we leverage these resources to systematically investigate the presence of mutation-specific transcription markers in a wide variety of cancer lineages and genotypes. Sensitivity and specificity of potential transcriptional biomarkers were simultaneously analyzed in 19 cell lineages grouped into 228 categories based on the mutational genotypes of 12 cancer-related genes. Among a total of 1,455 category-specific expression patterns, the expression of cAMP phosphodiesterase-4D (PDE4D) with 11 isoforms, one of the PDE4(A-D) subfamilies, was predicted to be regulated by a mutant form of serine/threonine kinase 11 (STK11)/liver kinase B1 (LKB1) present in lung cancer. STK11/LKB1 is the primary upstream kinase of adenine monophosphate-activated protein kinase (AMPK). Subsequently, we found that the knockdown of PDE4D gene expression inhibited proliferation of STK11-mutated lung cancer lines. Furthermore, challenge with a panel of PDE4-specific inhibitors was shown to selectively reduce the growth of STK11-mutated lung cancer lines. Thus, we show that multidimensional analysis of a well-characterized large-scale panel of cancer cell lines provides unprecedented opportunities for the identification of unexpected oncogenic mechanisms and mutation-specific drug targets.
authors.affiliation: Center for Advanced Bioinformatics and Systems Medicine, Sookmyung Women's University, Seoul, Republic of Korea. Department of Biological Sciences, Sookmyung Women's University, Seoul, Republic of Korea.
authors.forename: Ningning
authors.initials: N
authors.lastname: He
authors.affiliation: Center for Advanced Bioinformatics and Systems Medicine, Sookmyung Women's University, Seoul, Republic of Korea. Department of Biological Sciences, Sookmyung Women's University, Seoul, Republic of Korea.
authors.forename: Nayoung
authors.initials: N
authors.lastname: Kim
authors.affiliation: Center for Advanced Bioinformatics and Systems Medicine, Sookmyung Women's University, Seoul, Republic of Korea.
authors.forename: Mee
authors.initials: M
authors.lastname: Song
authors.affiliation: Center for Advanced Bioinformatics and Systems Medicine, Sookmyung Women's University, Seoul, Republic of Korea.
authors.forename: Choa
authors.initials: C
authors.lastname: Park
authors.affiliation: Center for Advanced Bioinformatics and Systems Medicine, Sookmyung Women's University, Seoul, Republic of Korea.
authors.forename: Somin
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Biological Sciences, Sookmyung Women's University, Seoul, Republic of Korea.
authors.forename: Eun Young
authors.initials: EY
authors.lastname: Park
authors.affiliation: Department of Biological Sciences, Sookmyung Women's University, Seoul, Republic of Korea.
authors.forename: Hwa Young
authors.initials: HY
authors.lastname: Yim
authors.affiliation: Department of Statistics, Sookmyung Women's University, Seoul, Republic of Korea.
authors.forename: Kyunga
authors.initials: K
authors.lastname: Kim
authors.affiliation: Department of Biological Sciences, Sookmyung Women's University, Seoul, Republic of Korea.
authors.forename: Jong Hoon
authors.initials: JH
authors.lastname: Park
authors.affiliation: Department of Biological Sciences, Sookmyung Women's University, Seoul, Republic of Korea.
authors.forename: Keun Il
authors.initials: KI
authors.lastname: Kim
authors.affiliation: Systems Biology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Systems Biology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.affiliation: Center for Advanced Bioinformatics and Systems Medicine, Sookmyung Women's University, Seoul, Republic of Korea. Department of Biological Sciences, Sookmyung Women's University, Seoul, Republic of Korea. yoonsj@sookmyung.ac.kr.
authors.forename: Sukjoon
authors.initials: S
authors.lastname: Yoon
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism*; D000091162:AMP-Activated Protein Kinase Kinases; D017209:Apoptosis / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D059467:Transcriptome; D014162:Transfection
chemical_list: D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517376:PDE4D protein, human