STANDARD_NAME CERVERA_SDHB_TARGETS_1_DN SYSTEMATIC_NAME M11404 COLLECTION C2:CGP MSIGDB_URL https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/CERVERA_SDHB_TARGETS_1_DN NAMESPACE AFFY_HG_U133 DESCRIPTION_BRIEF Genes turned off in Hep3B cells (hepatocellular carcinoma, HCC) upon knockdown of SDHB [GeneID=6390] by RNAi. DESCRIPTION_FULL Recently, enzymes of the tricarboxylic acid (TCA) cycle have emerged as novel tumor suppressors. In particular, mutations in the nuclear-encoded subunits of succinate dehydrogenase (SDHB, SDHC, and SDHD) cause paragangliomas and pheochromocytomas. Although the mechanism(s) by which disruption of mitochondrial metabolism leads to neoplasia is largely unknown, increasing evidence points to an activation of pseudohypoxia. In this study, we have shown that silencing of SDHB using DNA-based small interfering RNA resulted in major impairments in cellular proliferation, respiration, and a corresponding shift to glycolysis. The levels of reactive oxygen species, however, were unchanged. As expected, hypoxia-inducible factor-1 alpha (HIF-1 alpha) and HIF-2alpha were up-regulated in chronically silenced cells, suggesting that a pseudohypoxic state was attained. In addition, the c-Jun amino-terminal kinase and p38 kinase stress signaling proteins were hyperphosphorylated in SDHB-silenced cells. Microarray analysis showed that >400 genes were influenced (6-fold or more up-regulation or down-regulation) by silencing of SDHB, confirming the importance of the TCA cycle in cellular metabolism. Examples of dysregulated genes included those involved in proliferation, adhesion, and the hypoxia pathway. Of interest, SDHB-silenced cells had a greater capacity to adhere to extracellular matrix components, including fibronectin and laminin, than control cells, thus suggesting a possible mechanism of tumor initiation. Although transient silencing of the HIF-1 alpha transcription factor in SDHB-silenced cells had little effect on the expression of a subset of up-regulated genes, it partially reversed the adhesion phenotype to fibronectin, pointing to a potentially important role for HIF-1 in this process. PMID 18519664 GEOID GSE10289 AUTHORS Cervera AM,Apostolova N,Crespo FL,Mata M,McCreath KJ CONTRIBUTOR Jessica Robertson CONTRIBUTOR_ORG MSigDB Team EXACT_SOURCE Table 2BS FILTERED_BY_SIMILARITY EXTERNAL_NAMES_FOR_SIMILAR_TERMS EXTERNAL_DETAILS_URL SOURCE_MEMBERS 1565758_at,1568603_at,1568604_a_at,200799_at,202022_at,202661_at,204607_at,204694_at,204920_at,205697_at,205754_at,205883_at,206000_at,206214_at,206292_s_at,206983_at,209243_s_at,212092_at,212094_at,212841_s_at,213479_at,213975_s_at,214261_s_at,219415_at,219522_at,219867_at,220604_x_at,222760_at,223614_at,223979_x_at,224300_x_at,224507_s_at,227353_at,227762_at,228038_at,228461_at,228507_at,228647_at,228854_at,229160_at,229819_at,231667_at,231693_at,236300_at,238877_at,243799_x_at GENE_SYMBOLS ,CADPS,CADPS,HSPA1A,ALDOC,ITPR2,HMGCS2,AFP,CPS1,SCGN,F2,ZBTB16,MEP1A,PLA2G7,SULT2A1,CCR6,PEG3,PEG10,PEG10,PPFIBP2,NPTX2,LYZ,ADH6,TTYH1,FJX1,CHODL,FTCD,ZNF703,MMP16,FTCD,FTCD,,TMC8,ZBTB16,SOX2,SH3RF3,PDE3A,NINJ2-AS1,ZBTB16,PWWP3B,A1BG,SLC39A5,,PDE3A,EYA4,ANGPTL3 FOUNDER_NAMES