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Series GSE153499 Query DataSets for GSE153499
Status Public on Dec 07, 2020
Title Protein synthesis inhibitors stimulate MondoA transcriptional activity by driving accumulation of glucose 6-phosphate
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary BACKGROUND: Protein synthesis is regulated by the availability of amino acids, the engagement of growth factor signaling pathways and ATP levels sufficient to support translation. Crosstalk between these inputs is extensive, yet other regulatory mechanisms remain to be characterized. For example, the translation initiation inhibitor Rocaglamide A (RocA) induces Thioredoxin Interacting Protein (TXNIP). TXNIP is a negative regulator of glucose uptake, thus its induction by RocA links translation to the availability of glucose. MondoA is the principal regulator of glucose-induced transcription and its activity is triggered by the glycolytic intermediate, glucose 6-phosphate (G6P). MondoA responds to G6P generated by cytoplasmic glucose and mitochondrial ATP (mtATP), suggesting a critical role in the cellular response to these energy sources. TXNIP expression is entirely dependent on MondoA, therefore, we investigated how protein synthesis inhibitors impact its transcriptional activity. METHODS: We investigated how translation regulates MondoA activity using cell line models and loss-of-function approaches. We examined how protein synthesis inhibitors effect gene expression and metabolism using RNA-sequencing and metabolomics, respectively. The biological impact of RocA was evaluated using both cell line models and Patient-Derived Xenograft Organoid models. RESULTS: We discovered that multiple protein synthesis inhibitors, including RocA, increase TXNIP expression in a manner that depends on MondoA, a functional electron transport chain and mtATP synthesis. Furthermore, RocA increases mtATP and G6P levels and TXNIP induction depends on interactions between the Voltage-Dependent Anion Channel (VDAC) and hexokinase, which generates G6P. RocA treatment impacts the regulation of ~1200 genes and ~250 of those genes are MondoA-dependent. RocA treatment is cytotoxic to Triple Negative Breast Cancer cell lines and shows preferential cytotoxicity against ER- patient-derived breast cancer models. Finally, RocA-driven cytotoxicity is partially-dependent on MondoA or TXNIP. CONCLUSION: Our data suggest that protein synthesis inhibitors rewire metabolism, resulting in an increase in mtATP and G6P, the latter driving MondoA-dependent transcriptional activity. Further, MondoA is a critical component of the cellular transcriptional response to RocA. Our functional assays suggest that RocA or similar translation inhibitors may show efficacy against ER- tumors and that the levels of MondoA and TXNIP should be considered when exploring these potential treatment options.
Overall design mRNA sequencing of HeLa and HeLa:MondoA-KO cells treated with DMSO or 100nM Rocaglamide A (RocA) for 4 hours
Web link
Contributor(s) Wilde BR, Kaadige MR, Guillen KP, Butterfield A, Welm BE, Ayer DE
Citation(s) 33292639
Submission date Jun 29, 2020
Last update date Dec 15, 2020
Contact name Donald E Ayer
Organization name University of Utah
Street address 2000 Circle of Hope
City Salt Lake City
State/province UT
ZIP/Postal code 84112
Country USA
Platforms (1)
GPL16791 Illumina HiSeq 2500 (Homo sapiens)
Samples (8)
GSM4645389 HeLa_DMSO rep1
GSM4645390 HeLa_DMSO rep2
GSM4645391 HeLa_RocA rep1
BioProject PRJNA642855
SRA SRP269226

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

Supplementary file Size Download File type/resource
GSE153499_RAW.tar 730.0 Kb (http)(custom) TAR (of TXT)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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