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| Status |
Public on Oct 22, 2016 |
| Title |
Nuclear TIGAR mediates an epigenetic-metabolic loop via Nrf2 for cancer therapeutics resistance |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Epigenetic and metabolic reprogrammings are implicated in cancer progression with unclear mechanisms. We report here that the histone methyltransferase NSD2 drives cancer cell and tumor resistance to therapeutics such as tamoxifen, doxorubicin, and radiation by reprogramming of glucose metabolism. NSD2 coordinately up-regulates expression of TIGAR, HK2 and G6PD and stimulates pentose phosphate pathway (PPP) production of NADPH for ROS reduction. We discover that elevated expression of TIGAR, previously characterized as a fructose-2,6-bisphosphatase, is localized in the nuclei of resistant tumor cells where it stimulates NSD2 expression and global H3K36me2 mark. Mechanistically, TIGAR interacts with the antioxidant regulator Nrf2 and facilitates chromatin assembly of Nrf2-H3K4me3 methylase MLL1 and elongating Pol-II, independent of its metabolic enzymatic activity. In human tumors, high levels of NSD2 correlate strongly with early recurrence and poor survival and are associated with nuclear-localized TIGAR. This study defines a nuclear TIGAR-mediated, epigenetic autoregulatory loop functioning in redox rebalance for resistance to tumor therapeutics.
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| Overall design |
A total of 4 samples were analyzed in this study. The study included two cell lines, MCF7 and the tamoxifen-resistant subline TMR. Both were were cultured in medium containing vehicle control and/or 4-hydroxytamoxifen (Tam). The untreated MCF7 and TMR cell lines served as controls for the study.
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| Contributor(s) |
Chen H, Wang J, Tepper CG |
| Citation(s) |
27164560 |
| NIH grant(s) |
| Grant ID |
Grant title |
Affiliation |
Name |
| P30 CA093373 |
CANCER CENTER SUPPORT GRANT-P30: Cancer Center Support Grant - P30: Cancer Center Support Grant - P30: Cancer Center Support Grant - P30: Cancer Center Support Grant - P30: Cancer Center Support Grant - P30: Cancer Center Support Grant - P30: Cancer Center Support Grant - P30: Cancer Center Support Grant - P30: Cancer Center Support Grant - P30: Cancer Center Support Grant - P30: Cancer Center Support Grant - P30: Cancer Center Support Grant - P30: Cancer Center Support Grant - P30: Cancer Center Support Grant - P30: Cancer Center Support Grant - P30: Cancer Center Support Grant - P30: Cancer Center Support Grant - P30: Cancer Center Support Grant-P30: Cancer Center Support Grant-P30: Cancer Center Support Grant-P30: Cancer Center Support Grant-P30: Cancer Center Support Grant-P30: Cancer Center Support Grant-P30: Cancer Center Support Grant-P30: Cancer Center Support Grant-P30: Cancer Center Support Grant-P30: Cancer Center Support Grant-P30: Cancer Center Support Grant-P30 |
UNIVERSITY OF CALIFORNIA DAVIS |
Ralph W. deVere White |
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| Submission date |
Oct 22, 2014 |
| Last update date |
May 15, 2019 |
| Contact name |
Clifford G. Tepper |
| E-mail(s) |
cgtepper@ucdavis.edu
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| Phone |
916-734-7195
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| Organization name |
UC Davis School of Medicine
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| Department |
Biochemistry and Molecular Medicine
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| Street address |
4645 2nd Avenue, Room 2300A
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| City |
Sacramento |
| State/province |
CA |
| ZIP/Postal code |
95817 |
| Country |
USA |
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| Platforms (1) |
| GPL11154 |
Illumina HiSeq 2000 (Homo sapiens) |
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| Samples (4)
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| Relations |
| BioProject |
PRJNA264542 |
| SRA |
SRP049171 |
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