Restoring the Epigenetically Silenced PCK2 Suppresses Renal Cell Carcinoma Progression and Increases Sensitivity to Sunitinib by Promoting Endoplasmic Reticulum Stress

Overview

Journal Theranostics

Date 2020 Oct 14

PMID 33052225

Citations 16

Authors

Zhiyong Xiong

Changfei Yuan

Jian Shi

Wei Xiong

Yu Huang

Wen Xiao

Hongmei Yang

Ke Chen

Xiaoping Zhang

Affiliations

Soon will be listed here.

Abstract

Tumors have significant abnormalities in various biological properties. In renal cell carcinoma (RCC), metabolic abnormalities are characteristic biological dysfunction that cannot be ignored. Despite this, many aspects of this dysfunction have not been fully explained. The purpose of this study was to reveal a new mechanism of metabolic and energy-related biological abnormalities in RCC. Molecular screening and bioinformatics analysis were performed in RCC based on data from The Cancer Genome Atlas (TCGA) database. Regulated pathways were investigated by qRT-PCR, immunoblot analysis and immunohistochemistry. A series of functional analyses was performed in cell lines and xenograft models. By screening the biological abnormality core dataset-mitochondria-related dataset and the metabolic abnormality core dataset-energy metabolism-related dataset in public RCC databases, PCK2 was found to be differentially expressed in RCC compared with normal tissue. Further analysis by the TCGA database showed that PCK2 was significantly downregulated in RCC and predicted a poor prognosis. Through additional studies, it was found that a low expression of PCK2 in RCC was caused by methylation of its promoter region. Restoration of PCK2 expression in RCC cells repressed tumor progression and increased their sensitivity to sunitinib. Finally, mechanistic investigations indicated that PCK2 mediated the above processes by promoting endoplasmic reticulum stress. Collectively, our results identify a specific mechanism by which PCK2 suppresses the progression of renal cell carcinoma (RCC) and increases sensitivity to sunitinib by promoting endoplasmic reticulum stress. This finding provides a new biomarker for RCC as well as novel targets and strategies for the treatment of RCC.

Citing Articles

Phosphoenolpyruvate carboxykinase 2 is a promising prognostic biomarker that correlates with peritumoral dendritic cell infiltration in glioblastoma.

Yi L, Jiang C, Guo P, Zhu W, Jiang X J Cancer. 2025; 16(2):590-602.

PMID: 39744481 PMC: 11685687. DOI: 10.7150/jca.97034.

Oxidative and Endoplasmic Reticulum Stress Mediate Testicular Injury in a Rat Model of Varicocele.

Tang L, Tang L, Guo X, Wen S, Duan Z, Zhong X Reprod Sci. 2024; .

PMID: 39638967 DOI: 10.1007/s43032-024-01749-8.

Screening of functional genes for hypoxia adaptation in Tibetan pigs by combined genome resequencing and transcriptome analysis.

Ni B, Tang L, Zhu L, Li X, Zhang K, Nie H Front Vet Sci. 2024; 11:1486258.

PMID: 39497743 PMC: 11532106. DOI: 10.3389/fvets.2024.1486258.

Phosphoenolpyruvate carboxykinase 2-mediated metabolism promotes lung tumorigenesis by inhibiting mitochondrial-associated apoptotic cell death.

Zhang J, He W, Liu D, Zhang W, Qin H, Zhang S Front Pharmacol. 2024; 15:1434988.

PMID: 39193344 PMC: 11347759. DOI: 10.3389/fphar.2024.1434988.

Decoding sunitinib resistance in ccRCC: Metabolic-reprogramming-induced ABAT and GABAergic system shifts.

Zhang Q, Ding L, Yan Y, Zhai Q, Guo Z, Li Y iScience. 2024; 27(7):110415.

PMID: 39100925 PMC: 11295714. DOI: 10.1016/j.isci.2024.110415.

References

Zhao T, Bao Y, Gan X, Wang J, Chen Q, Dai Z . DNA methylation-regulated QPCT promotes sunitinib resistance by increasing HRAS stability in renal cell carcinoma. Theranostics. 2019; 9(21):6175-6190. PMC: 6735520. DOI: 10.7150/thno.35572. View

Liu J, Wang Y, Song L, Zeng L, Yi W, Liu T . A critical role of DDRGK1 in endoplasmic reticulum homoeostasis via regulation of IRE1α stability. Nat Commun. 2017; 8:14186. PMC: 5290148. DOI: 10.1038/ncomms14186. View

Hetz C . The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol. 2012; 13(2):89-102. DOI: 10.1038/nrm3270. View

Siegel R, Miller K, Jemal A . Cancer statistics, 2019. CA Cancer J Clin. 2019; 69(1):7-34. DOI: 10.3322/caac.21551. View

Bergers G, Hanahan D . Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer. 2008; 8(8):592-603. PMC: 2874834. DOI: 10.1038/nrc2442. View

Molnar Z, Banlaki Z, Somogyi A, Herold Z, Herold M, Guttman A . Diabetes-specific Modulation of Peripheral Blood Gene Expression Signatures in Colorectal Cancer. Curr Mol Med. 2020; 20(10):773-780. DOI: 10.2174/1566524020666200504084626. View

Vincent E, Sergushichev A, Griss T, Gingras M, Samborska B, NTimbane T . Mitochondrial Phosphoenolpyruvate Carboxykinase Regulates Metabolic Adaptation and Enables Glucose-Independent Tumor Growth. Mol Cell. 2015; 60(2):195-207. DOI: 10.1016/j.molcel.2015.08.013. View

Hu C, Mohtat D, Yu Y, Ko Y, Shenoy N, Bhattacharya S . Kidney cancer is characterized by aberrant methylation of tissue-specific enhancers that are prognostic for overall survival. Clin Cancer Res. 2014; 20(16):4349-60. PMC: 4424050. DOI: 10.1158/1078-0432.CCR-14-0494. View

Zhu H, Wu K, Yan W, Ling Hu , Yuan J, Dong Y . Epigenetic silencing of DACH1 induces loss of transforming growth factor-β1 antiproliferative response in human hepatocellular carcinoma. Hepatology. 2013; 58(6):2012-22. DOI: 10.1002/hep.26587. View

10.

Jones P, Baylin S . The fundamental role of epigenetic events in cancer. Nat Rev Genet. 2002; 3(6):415-28. DOI: 10.1038/nrg816. View

11.

Beale E, Harvey B, Forest C . PCK1 and PCK2 as candidate diabetes and obesity genes. Cell Biochem Biophys. 2007; 48(2-3):89-95. DOI: 10.1007/s12013-007-0025-6. View

12.

Qiu B, Ackerman D, Sanchez D, Li B, Ochocki J, Grazioli A . HIF2α-Dependent Lipid Storage Promotes Endoplasmic Reticulum Homeostasis in Clear-Cell Renal Cell Carcinoma. Cancer Discov. 2015; 5(6):652-67. PMC: 4456212. DOI: 10.1158/2159-8290.CD-14-1507. View

13.

Feinberg A, Koldobskiy M, Gondor A . Epigenetic modulators, modifiers and mediators in cancer aetiology and progression. Nat Rev Genet. 2016; 17(5):284-99. PMC: 4888057. DOI: 10.1038/nrg.2016.13. View

14.

Nakamura R, Oyama T, Tajiri R, Mizokami A, Namiki M, Nakamoto M . Expression and regulatory effects on cancer cell behavior of NELL1 and NELL2 in human renal cell carcinoma. Cancer Sci. 2015; 106(5):656-64. PMC: 4452169. DOI: 10.1111/cas.12649. View

15.

Wettersten H, Abu Aboud O, Lara Jr P, Weiss R . Metabolic reprogramming in clear cell renal cell carcinoma. Nat Rev Nephrol. 2017; 13(7):410-419. DOI: 10.1038/nrneph.2017.59. View

16.

Rini B, Campbell S, Escudier B . Renal cell carcinoma. Lancet. 2009; 373(9669):1119-32. DOI: 10.1016/S0140-6736(09)60229-4. View

17.

Zahir N, Sun R, Gallahan D, Gatenby R, Curtis C . Characterizing the ecological and evolutionary dynamics of cancer. Nat Genet. 2020; 52(8):759-767. DOI: 10.1038/s41588-020-0668-4. View

18.

Cook K, Figg W . Angiogenesis inhibitors: current strategies and future prospects. CA Cancer J Clin. 2010; 60(4):222-43. PMC: 2919227. DOI: 10.3322/caac.20075. View

19.

Du Z, Li L, Huang X, Jin J, Huang S, Zhang Q . The epigenetic modifier CHD5 functions as a novel tumor suppressor for renal cell carcinoma and is predominantly inactivated by promoter CpG methylation. Oncotarget. 2016; 7(16):21618-30. PMC: 5008310. DOI: 10.18632/oncotarget.7822. View

20.

Yang Q, Wang Y, Yang Q, Gao Y, Duan X, Fu Q . Cuprous oxide nanoparticles trigger ER stress-induced apoptosis by regulating copper trafficking and overcoming resistance to sunitinib therapy in renal cancer. Biomaterials. 2017; 146:72-85. DOI: 10.1016/j.biomaterials.2017.09.008. View