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Series GSE158833 Query DataSets for GSE158833
Status Public on Sep 20, 2022
Title Translational activation of ATF4 through mitochondrial anaplerotic metabolic pathways is required for DLBCL growth and survival
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary Cancer cells frequently hijack adaptive stress response signals/pathways to protect themselves from metabolic or genetic vulnerabilities, pointing to candidate therapeutic targets. Among these SIRT3 was recently identified as a non-oncogene addiction mechanism in DLBCL through its role in glutamine metabolism. Here, we investigated downstream signaling pathways linked to SIRT3 function in lymphoma. We performed RNA-seq in DLBCL cells after SIRT3 knockdown and observed that ATF4 target genes were significantly downregulated in SIRT3 deficient cells. ATF4, a master regulator of cellular stress, was required to maintain proliferation and survival of DLBCL cells and its target genes were overexpressed in DLBCL patients as compared to normal germinal center B cells. Translation of ATF4 mRNA was inhibited in SIRT3 knockdown cells and expression of exogenous ATF4 partially rescued cell proliferation and viability inhibited by SIRT3 deficiency. Accordingly, ATF4 protein was expressed at relatively lower levels SIRT3 deficient murine lymphomas, whereas its higher expression was associated with more severe disease. We characterized mechanisms through which SIRT3 maintains ATF4 expression, downstream of its effects on glutamine entry into the TCA cycle and suppression of autophagy. Specifically, loss of SIRT3 disrupted amino acid metabolism in DLBCL cells, with subsequent impairment of ATF4 response to metabolic stressors such as glutamine depletion. Collectively, the data suggest a key SIRT3-ATF4 axis maintains survival of DLBCL cells enabling them to optimize amino acid metabolism and cope with metabolic vulnerabilities possibly associated with their high proliferative rate.
 
Overall design RNAseq following shRNA knockdown of SIRT3 in DLBCL cell lines
 
Contributor(s) Li M, Teater M, Melnick AM
Citation(s) 35019856
Submission date Sep 30, 2020
Last update date Sep 22, 2022
Contact name Matt Teater
E-mail(s) mrt2001@med.cornell.edu
Organization name Weill Cornell Medical College
Street address 445 E 69th St
City New York
State/province NY
ZIP/Postal code 10021
Country USA
 
Platforms (1)
GPL16791 Illumina HiSeq 2500 (Homo sapiens)
Samples (27)
GSM4811733 Sample_1_Karpas422_shCTRL_R1
GSM4811734 Sample_2_Karpas422_shCTRL_R2
GSM4811735 Sample_3_Karpas422_shCTRL_R3
Relations
BioProject PRJNA666669
SRA SRP285934

Download family Format
SOFT formatted family file(s) SOFTHelp
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Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE158833_RAW.tar 5.7 Mb (http)(custom) TAR (of TXT)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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