PGC1 Alpha Coactivates ERG Fusion to Drive Antioxidant Target Genes Under Metabolic Stress

Overview

Journal Commun Biol

Specialty Biology

Date 2022 May 4

PMID 35508713

Authors

Aiindrila Dhara

Imlimaong Aier

Ankush Paladhi

Pritish Kumar Varadwaj

Sumit Kumar Hira

Nirmalya Sen

Affiliations

Soon will be listed here.

Abstract

The presence of ERG gene fusion; from developing prostatic intraepithelial neoplasia (PIN) lesions to hormone resistant high grade prostate cancer (PCa) dictates disease progression, altered androgen metabolism, proliferation and metastasis. ERG driven transcriptional landscape may provide pro-tumorigenic cues in overcoming various strains like hypoxia, nutrient deprivation, inflammation and oxidative stress. However, insights on the androgen independent regulation and function of ERG during stress are limited. Here, we identify PGC1α as a coactivator of ERG fusion under various metabolic stress. Deacetylase SIRT1 is necessary for PGC1α-ERG interaction and function. We reveal that ERG drives the expression of antioxidant genes; SOD1 and TXN, benefitting PCa growth. We observe increased expression of these antioxidant genes in patients with high ERG expression correlates with poor survival. Inhibition of PGC1α-ERG axis driven transcriptional program results in apoptosis and reduction in PCa xenografts. Here we report a function of ERG under metabolic stress which warrants further studies as a therapeutic target for ERG fusion positive PCa.

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References

Shukla S, Cyrta J, Murphy D, Walczak E, Ran L, Agrawal P . Aberrant Activation of a Gastrointestinal Transcriptional Circuit in Prostate Cancer Mediates Castration Resistance. Cancer Cell. 2017; 32(6):792-806.e7. PMC: 5728174. DOI: 10.1016/j.ccell.2017.10.008. View

Aykin-Burns N, Ahmad I, Zhu Y, Oberley L, Spitz D . Increased levels of superoxide and H2O2 mediate the differential susceptibility of cancer cells versus normal cells to glucose deprivation. Biochem J. 2008; 418(1):29-37. PMC: 2678564. DOI: 10.1042/BJ20081258. View

Eidelman E, Twum-Ampofo J, Ansari J, Siddiqui M . The Metabolic Phenotype of Prostate Cancer. Front Oncol. 2017; 7:131. PMC: 5474672. DOI: 10.3389/fonc.2017.00131. View

Martens J, Mandoli A, Simmer F, Wierenga B, Saeed S, Singh A . ERG and FLI1 binding sites demarcate targets for aberrant epigenetic regulation by AML1-ETO in acute myeloid leukemia. Blood. 2012; 120(19):4038-48. PMC: 3496958. DOI: 10.1182/blood-2012-05-429050. View

Hansen A, Sandsmark E, Rye M, Wright A, Bertilsson H, Richardsen E . Presence of TMPRSS2-ERG is associated with alterations of the metabolic profile in human prostate cancer. Oncotarget. 2016; 7(27):42071-42085. PMC: 5173117. DOI: 10.18632/oncotarget.9817. View

Puigserver P, Adelmant G, Wu Z, Fan M, Xu J, OMalley B . Activation of PPARgamma coactivator-1 through transcription factor docking. Science. 1999; 286(5443):1368-71. DOI: 10.1126/science.286.5443.1368. View

Papa L, Manfredi G, Germain D . SOD1, an unexpected novel target for cancer therapy. Genes Cancer. 2014; 5(1-2):15-21. PMC: 4063254. DOI: 10.18632/genesandcancer.4. View

Harris I, Treloar A, Inoue S, Sasaki M, Gorrini C, Lee K . Glutathione and thioredoxin antioxidant pathways synergize to drive cancer initiation and progression. Cancer Cell. 2015; 27(2):211-22. DOI: 10.1016/j.ccell.2014.11.019. View

Bader D, Hartig S, Putluri V, Foley C, Hamilton M, Smith E . Mitochondrial pyruvate import is a metabolic vulnerability in androgen receptor-driven prostate cancer. Nat Metab. 2019; 1(1):70-85. PMC: 6563330. DOI: 10.1038/s42255-018-0002-y. View

10.

Shao Y, Ye G, Ren S, Piao H, Zhao X, Lu X . Metabolomics and transcriptomics profiles reveal the dysregulation of the tricarboxylic acid cycle and related mechanisms in prostate cancer. Int J Cancer. 2018; 143(2):396-407. DOI: 10.1002/ijc.31313. View

11.

Ahmad I, Aykin-Burns N, Sim J, Walsh S, Higashikubo R, Buettner G . Mitochondrial O2*- and H2O2 mediate glucose deprivation-induced stress in human cancer cells. J Biol Chem. 2004; 280(6):4254-63. DOI: 10.1074/jbc.M411662200. View

12.

Flajollet S, Tian T, Flourens A, Tomavo N, Villers A, Bonnelye E . Abnormal expression of the ERG transcription factor in prostate cancer cells activates osteopontin. Mol Cancer Res. 2011; 9(7):914-24. DOI: 10.1158/1541-7786.MCR-10-0537. View

13.

Freedland S, Mavropoulos J, Wang A, Darshan M, Demark-Wahnefried W, Aronson W . Carbohydrate restriction, prostate cancer growth, and the insulin-like growth factor axis. Prostate. 2007; 68(1):11-9. PMC: 3959866. DOI: 10.1002/pros.20683. View

14.

Shiota M, Yokomizo A, Tada Y, Inokuchi J, Tatsugami K, Kuroiwa K . Peroxisome proliferator-activated receptor gamma coactivator-1alpha interacts with the androgen receptor (AR) and promotes prostate cancer cell growth by activating the AR. Mol Endocrinol. 2009; 24(1):114-27. PMC: 5428145. DOI: 10.1210/me.2009-0302. View

15.

Lin J, Handschin C, Spiegelman B . Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab. 2005; 1(6):361-70. DOI: 10.1016/j.cmet.2005.05.004. View

16.

Girnun G . The diverse role of the PPARγ coactivator 1 family of transcriptional coactivators in cancer. Semin Cell Dev Biol. 2012; 23(4):381-8. PMC: 3369022. DOI: 10.1016/j.semcdb.2012.01.007. View

17.

Tan Z, Luo X, Xiao L, Tang M, Bode A, Dong Z . The Role of PGC1α in Cancer Metabolism and its Therapeutic Implications. Mol Cancer Ther. 2016; 15(5):774-82. DOI: 10.1158/1535-7163.MCT-15-0621. View

18.

Sorensen P, Lessnick S, Liu X, Triche T, Denny C . A second Ewing's sarcoma translocation, t(21;22), fuses the EWS gene to another ETS-family transcription factor, ERG. Nat Genet. 1994; 6(2):146-51. DOI: 10.1038/ng0294-146. View

19.

Valcarcel-Jimenez L, Macchia A, Crosas-Molist E, Schaub-Clerigue A, Camacho L, Martin-Martin N . PGC1α Suppresses Prostate Cancer Cell Invasion through ERRα Transcriptional Control. Cancer Res. 2019; 79(24):6153-6165. DOI: 10.1158/0008-5472.CAN-19-1231. View

20.

Vijayaraj P, Le Bras A, Mitchell N, Kondo M, Juliao S, Wasserman M . Erg is a crucial regulator of endocardial-mesenchymal transformation during cardiac valve morphogenesis. Development. 2012; 139(21):3973-85. PMC: 3472597. DOI: 10.1242/dev.081596. View