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Journal of Experimental & Clinical Cancer Research

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Open Access 01-12-2021 | Research

A HIF1α-GPD1 feedforward loop inhibits the progression of renal clear cell carcinoma via mitochondrial function and lipid metabolism

Authors: Ren Liu, Yuanfa Feng, Yulin Deng, Zhihao Zou, Jianheng Ye, Zhiduan Cai, Xuejin Zhu, Yingke Liang, Jianming Lu, Hui Zhang, Yong Luo, Zhaodong Han, Yangjia Zhuo, Qingling Xie, Chi Tin Hon, Yuxiang Liang, Chin-Lee Wu, Weide Zhong

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2021

Abstract

Background

Hypoxia signaling, especially the hypoxia inducible factor (HIF) pathway, is a major player in clear cell renal cell carcinoma (ccRCC), which is characterized by disorders in lipid and glycogen metabolism. However, the interaction between hypoxia and lipid metabolism in ccRCC progression is still poorly understood.

Methods

We used bioinformatic analysis and discovered that glycerol-3-phosphate dehydrogenase 1 (GPD1) may play a key role in hypoxia and lipid metabolism pathways in ccRCC. Tissue microarray, IHC staining, and survival analysis were performed to evaluate clinical function. In vitro and in vivo assays showed the biological effects of GPD1 in ccRCC progression.

Results

We found that the expression of GPD1 was downregulated in ccRCC tissues, and overexpression of GPD1 inhibited the progression of ccRCC both in vivo and in vitro. Furthermore, we demonstrated that hypoxia inducible factor-1α (HIF1α) directly regulates GPD1 at the transcriptional level, which leads to the inhibition of mitochondrial function and lipid metabolism. Additionally, GPD1 was shown to inhibit prolyl hydroxylase 3 (PHD3), which blocks prolyl-hydroxylation of HIF1α and subsequent proteasomal degradation, and thus reinforces the inhibition of mitochondrial function and phosphorylation of AMPK via suppressing glycerol-3-phosphate dehydrogenase 2 (GPD2).

Conclusions

This study not only demonstrated that HIF1α-GPD1 forms a positive feedforward loop inhibiting mitochondrial function and lipid metabolism in ccRCC, but also discovered a new mechanism for the molecular basis of HIF1α to inhibit tumor activity, thus providing novel insights into hypoxia-lipid-mediated ccRCC therapy.

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Moch H, Cubilla AL, Humphrey PA, Reuter VE, Ulbright TM. The 2016 WHO classification of Tumours of the urinary system and male genital organs-part a: renal, penile, and testicular Tumours. Eur Urol. 2016;70(1):93–105. https://doi.org/10.1016/j.eururo.2016.02.029.CrossRefPubMed

Du W, et al. HIF drives lipid deposition and cancer in ccRCC via repression of fatty acid metabolism. Nat Commun. 2017;8(1):1769. https://doi.org/10.1038/s41467-017-01965-8.CrossRefPubMedPubMedCentral

Hakimi AA, Reznik E, Lee CH, Creighton CJ, Brannon AR, Luna A, et al. An integrated metabolic atlas of clear cell renal cell carcinoma. Cancer Cell. 2016;29(1):104–16. https://doi.org/10.1016/j.ccell.2015.12.004.CrossRefPubMedPubMedCentral

Shen C, Beroukhim R, Schumacher SE, Zhou J, Chang M, Signoretti S, et al. Genetic and functional studies implicate HIF1alpha as a 14q kidney cancer suppressor gene. Cancer Discov. 2011;1(3):222–35. https://doi.org/10.1158/2159-8290.CD-11-0098.CrossRefPubMedPubMedCentral

Hoefflin R, Harlander S, Schäfer S, Metzger P, Kuo F, Schönenberger D, et al. HIF-1alpha and HIF-2alpha differently regulate tumour development and inflammation of clear cell renal cell carcinoma in mice. Nat Commun. 2020;11(1):4111. https://doi.org/10.1038/s41467-020-17873-3.CrossRefPubMedPubMedCentral

Melendez-Rodriguez F, et al. HIF1alpha suppresses tumor cell proliferation through inhibition of aspartate biosynthesis. Cell Rep. 2019;26(9):2257–65 e4. https://doi.org/10.1016/j.celrep.2019.01.106.CrossRefPubMed

Schodel J, et al. Hypoxia, hypoxia-inducible transcription factors, and renal Cancer. Eur Urol. 2016;69(4):646–57. https://doi.org/10.1016/j.eururo.2015.08.007.CrossRefPubMed

Saito K, Arai E, Maekawa K, Ishikawa M, Fujimoto H, Taguchi R, et al. Lipidomic signatures and associated transcriptomic profiles of clear cell renal cell carcinoma. Sci Rep. 2016;6(1):28932. https://doi.org/10.1038/srep28932.CrossRefPubMedPubMedCentral

Swierczynski J, Zabrocka L, Goyke E, Raczynska S, Adamonis W, Sledzinski Z. Enhanced glycerol 3-phosphate dehydrogenase activity in adipose tissue of obese humans. Mol Cell Biochem. 2003;254(1–2):55–9. https://doi.org/10.1023/A:1027332523114.CrossRefPubMed

10.

Eto K, Kadowaki T. Role of the NADH shuttle system in glucose-induced insulin secretion. Nihon Rinsho. 1999;57(3):503–14.PubMed

11.

Mracek T, Drahota Z, Houstek J. The function and the role of the mitochondrial glycerol-3-phosphate dehydrogenase in mammalian tissues. Biochim Biophys Acta. 2013;1827(3):401–10. https://doi.org/10.1016/j.bbabio.2012.11.014.CrossRefPubMed

12.

Madiraju AK, Erion DM, Rahimi Y, Zhang XM, Braddock DT, Albright RA, et al. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature. 2014;510(7506):542–6. https://doi.org/10.1038/nature13270.CrossRefPubMedPubMedCentral

13.

Thakur S, Daley B, Gaskins K, Vasko VV, Boufraqech M, Patel D, et al. Metformin targets mitochondrial Glycerophosphate dehydrogenase to control rate of oxidative phosphorylation and growth of thyroid Cancer in vitro and in vivo. Clin Cancer Res. 2018;24(16):4030–43. https://doi.org/10.1158/1078-0432.CCR-17-3167.CrossRefPubMedPubMedCentral

14.

Xie J, Ye J, Cai Z, Luo Y, Zhu X, Deng Y, et al. GPD1 enhances the anticancer effects of metformin by synergistically increasing Total cellular Glycerol-3-phosphate. Cancer Res. 2020;80(11):2150–62. https://doi.org/10.1158/0008-5472.CAN-19-2852.CrossRefPubMed

15.

Balabanov S, Zimmermann U, Protzel C, Scharf C, Klebingat KJ, Walther R. Tumour-related enzyme alterations in the clear cell type of human renal cell carcinoma identified by two-dimensional gel electrophoresis. Eur J Biochem. 2001;268(22):5977–80. https://doi.org/10.1046/j.0014-2956.2001.02546.x.CrossRefPubMed

16.

Cai Z, Deng Y, Ye J, Zhuo Y, Liu Z, Liang Y, et al. Aberrant expression of citrate synthase is linked to disease progression and clinical outcome in prostate Cancer. Cancer Manag Res. 2020;12:6149–63. https://doi.org/10.2147/CMAR.S255817.CrossRefPubMedPubMedCentral

17.

Simon N, Friedman J, Hastie T, Tibshirani R. Regularization paths for Cox's proportional hazards model via coordinate descent. J Stat Softw. 2011;39(5):1–13. https://doi.org/10.18637/jss.v039.i05.CrossRefPubMedPubMedCentral

18.

Zhang Y, Wang J, Liu X. LRRC19-A Bridge between Selenium Adjuvant Therapy and Renal Clear Cell Carcinoma: A Study Based on Datamining. Genes (Basel). 2020;11(4):440. Published 2020 Apr 17. https://doi.org/10.3390/genes11040440.

19.

Pflueger D, Mittmann C, Dehler S, Rubin MA, Moch H, Schraml P. Functional characterization of BC039389-GATM and KLK4-KRSP1 chimeric read-through transcripts which are up-regulated in renal cell cancer. BMC Genomics. 2015;16(1):247. https://doi.org/10.1186/s12864-015-1446-z.CrossRefPubMedPubMedCentral

20.

Morrissey JJ, Kharasch ED. The specificity of urinary aquaporin 1 and perilipin 2 to screen for renal cell carcinoma. J Urol. 2013;189(5):1913–20. https://doi.org/10.1016/j.juro.2012.11.034.CrossRefPubMed

21.

Hisazumi H, Nakajima K, Nishino A, Misaki T, Migita S. Pre- and post-operative changes of serum proteins in renal cancer patients. Hinyokika Kiyo. 1985;31(9):1519–23.PubMed

22.

Liu Y, Wang H, Ni B, Zhang J, Li S, Huang Y, et al. Loss of KCNJ15 expression promotes malignant phenotypes and correlates with poor prognosis in renal carcinoma. Cancer Manag Res. 2019;11:1211–20. https://doi.org/10.2147/CMAR.S184368.CrossRefPubMedPubMedCentral

23.

Mei J, Hu K, Peng X, Wang H, Liu C. Decreased expression of SLC16A12 mRNA predicts poor prognosis of patients with clear cell renal cell carcinoma. Medicine (Baltimore). 2019;98(30):e16624. https://doi.org/10.1097/MD.0000000000016624.CrossRef

24.

Takenawa J, Kaneko Y, Kishishita M, Higashitsuji H, Nishiyama H, Terachi T, et al. Transcript levels of aquaporin 1 and carbonic anhydrase IV as predictive indicators for prognosis of renal cell carcinoma patients after nephrectomy. Int J Cancer. 1998;79(1):1–7. https://doi.org/10.1002/(SICI)1097-0215(19980220)79:1<1::AID-IJC1>3.0.CO;2-5.CrossRefPubMed

25.

Chen ZF, Xiao YJ, Huang ZH, Chen T, Zhao SC, Jiang YD, et al. Quantitative and comparative proteomics analysis in clear cell renal cell carcinoma and adjacent noncancerous tissues by 2-D DIGE. Nan Fang Yi Ke Da Xue Xue Bao. 2017;37(11):1517–22.PubMed

26.

Galgano MT, Hampton GM, Frierson HF Jr. Comprehensive analysis of HE4 expression in normal and malignant human tissues. Mod Pathol. 2006;19(6):847–53. https://doi.org/10.1038/modpathol.3800612.CrossRefPubMed

27.

Rathmell WK, Rathmell JC, Linehan WM. Metabolic Pathways in Kidney Cancer: Current Therapies and Future Directions. J Clin Oncol. 2018 JCO2018792309. https://doi.org/10.1200/JCO.2018.79.2309. Epub ahead of print.

28.

Gordan JD, Bertout JA, Hu CJ, Diehl JA, Simon MC. HIF-2alpha promotes hypoxic cell proliferation by enhancing c-myc transcriptional activity. Cancer Cell. 2007;11(4):335–47. https://doi.org/10.1016/j.ccr.2007.02.006.CrossRefPubMedPubMedCentral

29.

Qiu B, Ackerman D, Sanchez DJ, Li B, Ochocki JD, Grazioli A, et al. HIF2alpha-dependent lipid storage promotes endoplasmic reticulum homeostasis in clear-cell renal cell carcinoma. Cancer Discov. 2015;5(6):652–67. https://doi.org/10.1158/2159-8290.CD-14-1507.CrossRefPubMedPubMedCentral

30.

Singh G. Mitochondrial FAD-linked Glycerol-3-phosphate dehydrogenase: a target for Cancer therapeutics. Pharmaceuticals (Basel). 2014;7(2):192–206. https://doi.org/10.3390/ph7020192.CrossRef

31.

Pecinova A, et al. Role of Mitochondrial Glycerol-3-Phosphate Dehydrogenase in Metabolic Adaptations of Prostate Cancer. Cells. 2020;9(8):1764. Published 2020 Jul 23. doi:10.3390/cells9081764

32.

Basel-Vanagaite L, Zevit N, Zahav AH, Guo L, Parathath S, Pasmanik-Chor M, et al. Transient infantile hypertriglyceridemia, fatty liver, and hepatic fibrosis caused by mutated GPD1, encoding glycerol-3-phosphate dehydrogenase 1. Am J Hum Genet. 2012;90(1):49–60. https://doi.org/10.1016/j.ajhg.2011.11.028.CrossRefPubMedPubMedCentral

Title: A HIF1α-GPD1 feedforward loop inhibits the progression of renal clear cell carcinoma via mitochondrial function and lipid metabolism
Authors: Ren Liu
Yuanfa Feng
Yulin Deng
Zhihao Zou
Jianheng Ye
Zhiduan Cai
Xuejin Zhu
Yingke Liang
Jianming Lu
Hui Zhang
Yong Luo
Zhaodong Han
Yangjia Zhuo
Qingling Xie
Chi Tin Hon
Yuxiang Liang
Chin-Lee Wu
Weide Zhong
Publication date: 01-12-2021
Publisher: BioMed Central
Published in: Journal of Experimental & Clinical Cancer Research / Issue 1/2021
Electronic ISSN: 1756-9966
DOI: https://doi.org/10.1186/s13046-021-01996-6

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