title: Lipid starvation and hypoxia synergistically activate ICAM1 and multiple genes in an Sp1-dependent manner to promote the growth of ovarian cancer.
abstract: BACKGROUND
  Elucidation of the molecular mechanisms by which cancer cells overcome hypoxia is potentially important for targeted therapy. Complexation of hypoxia-inducible factors (HIFs) with aryl hydrocarbon receptor nuclear translocators can enhance gene expression and initiate cellular responses to hypoxia. However, multiple molecular mechanisms may be required for cancer cells to adapt to diverse microenvironments. We previously demonstrated that a physical interaction between the ubiquitously expressed transcription factor Sp1 and HIF2 is a major cause of FVII gene activation in poor prognostic ovarian clear cell carcinoma (CCC) cells under hypoxia. Furthermore, it was found that FVII activation is synergistically enhanced when serum-starved cells are cultured under hypoxic conditions. In this study, we investigated whether HIFs and transcription factor Sp1 cooperate to activate multiple genes in CCC cells under conditions of serum starvation and hypoxia (SSH) and then contribute to malignant phenotypes.
  
  
  METHODS
  To identify genes activated under hypoxic conditions in an Sp1-dependent manner, we first performed cDNA microarray analyses. We further investigated the molecular mechanisms of synergistic gene activations including the associated serum factors by various experiments such as real-time RT-PCR, western blotting and chromatin immunoprecipitation. The study was further extended to animal experiments to investigate how it contributes to CCC progression in vivo.
  
  
  RESULTS
  ICAM1 is one such gene dramatically induced by SSH and is highly induced by SSH and its synergistic activation involves both the mTOR and autonomously activated TNFα-NFκB axes. We identified long chain fatty acids (LCFA) as a major class of lipids that is associated with albumin, a serum factor responsible for synergistic gene activation under SSH. Furthermore, we found that ICAM1 can be induced in vivo to promote tumor growth.
  
  
  CONCLUSIONS
  Sp1 and HIFs collaborate to activate genes required for the adaptation of CCC cells to severe microenvironments, such as LCFA starvation and hypoxia. This study highlights the importance of transcriptional regulation under lipid starvation and hypoxia in the promotion of CCC tumor growth.
authors: Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, 2-3-2 Nakao, Asahi-ku, Yokohama, 241-8515, Japan. skoizume@gancen.asahi.yokohama.jp.
authors: Shiro
authors: S
authors: Koizume
authors: Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, 2-3-2 Nakao, Asahi-ku, Yokohama, 241-8515, Japan. itoshim@ks.kyorin-u.ac.jp.
authors: Shin
authors: S
authors: Ito
authors: Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, 2-3-2 Nakao, Asahi-ku, Yokohama, 241-8515, Japan. nakayosi@gancen.asahi.yokohama.jp.
authors: Yoshiyasu
authors: Y
authors: Nakamura
authors: Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, 2-3-2 Nakao, Asahi-ku, Yokohama, 241-8515, Japan. mitsuyo@gancen.asahi.yokohama.jp.
authors: Mitsuyo
authors: M
authors: Yoshihara
authors: Departments of Pathology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan. mfuruya@yokohama-cu.ac.jp.
authors: Mitsuko
authors: M
authors: Furuya
authors: Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, 2-3-2 Nakao, Asahi-ku, Yokohama, 241-8515, Japan. roppeiyamada@yahoo.co.jp.
authors: Roppei
authors: R
authors: Yamada
authors: Obstetrics, Gynecology and Molecular Reproductive Science, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan. emiyagi@med.yokohama-cu.ac.jp.
authors: Etsuko
authors: E
authors: Miyagi
authors: Obstetrics, Gynecology and Molecular Reproductive Science, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan. hirafu@med.yokohama-cu.ac.jp.
authors: Fumiki
authors: F
authors: Hirahara
authors: Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, 2-3-2 Nakao, Asahi-ku, Yokohama, 241-8515, Japan. ytakano@gancen.asahi.yokohama.jp.
authors: Yasuo
authors: Y
authors: Takano
authors: Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, 2-3-2 Nakao, Asahi-ku, Yokohama, 241-8515, Japan. miyagi@gancen.asahi.yokohama.jp.
authors: Yohei
authors: Y
authors: Miyagi
mesh_terms: D049109:Cell Proliferation; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000860:Hypoxia / Q000235:genetics* / Q000378:metabolism*; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics*; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D011401:Promoter Regions, Genetic; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D015533:Transcriptional Activation; D047368:Tumor Burden; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D056811:Unfolded Protein Response
chemical_list: D005227:Fatty Acids; D051793:Hypoxia-Inducible Factor 1; D016328:NF-kappa B; D016329:Sp1 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D058570:TOR Serine-Threonine Kinases