The TGF-β/HDAC7 axis suppresses TCA cycle metabolism in renal cancer
Open accessAbstract
Mounting evidence points to alterations in mitochondrial metabolism in renal cell carcinoma (RCC). However, the mechanisms that regulate the TCA cycle in RCC remain uncharacterized. Here, we demonstrate that loss of TCA cycle enzyme expression is retained in RCC metastatic tissues. Moreover, proteomic analysis demonstrates that reduced TCA cycle enzyme expression is far more pronounced in RCC relative to other tumor types. Loss of TCA cycle enzyme expression is correlated with reduced expression of the transcription factor PGC-1α, which is also lost in RCC tissues. PGC-1α reexpression in RCC cells restores the expression of TCA cycle enzymes in vitro and in vivo and leads to enhanced glucose carbon incorporation into TCA cycle intermediates. Mechanistically, TGF-β signaling, in concert with histone deacetylase 7 (HDAC7), suppresses TCA cycle enzyme expression. Our studies show that pharmacologic inhibition of TGF-β restores the expression of TCA cycle enzymes and suppresses tumor growth in an orthotopic model of RCC. Taken together, this investigation reveals a potentially novel role for the TGF-β/HDAC7 axis in global suppression of TCA cycle enzymes in RCC and provides insight into the molecular basis of altered mitochondrial metabolism in this malignancy.
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These findings provide new insights into the epigenetic basis of altered mitochondrial metabolism in renal clear cell carcinoma.
“Altogether, these findings provide new insights into the epigenetic basis of altered mitochondrial metabolism in renal clear cell carcinoma (Nam et al., 2021).”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Nam et al., 2021
TGF-β uses HDAC7 as corepressor to switch off the expression of TCA enzymes.
“TGF-β uses HDAC7 as corepressor to switch off the expression of TCA enzymes.”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Nam et al., 2021
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Cites
Jemal, A., Murray, T., Ward, E., Samuels, A., Tiwari, R. C., Ghafoor, A., Feuer, E. J., & Thun, M. J. (2005) · CA A Cancer Journal for Clinicians · doi:10.3322/canjclin.55.1.10 · Cited by 5,433 · see citing works
Ivan, M., Kondo, K., Yang, H., Kim, W., Valiando, J., Ohh, M., Salic, A., Asara, J. M., Lane, W. S., & Kaelin Jr., W. G. (2001) · Science · doi:10.1126/science.1059817 · Cited by 4,735 · see citing works
Nieto, M. A., Huang, R. Y.-J., Jackson, R. A., & Thiery, J. P. (2016) · Cell · doi:10.1016/j.cell.2016.06.028 · Cited by 4,492 · see citing works
Massagué, J. (2008) · Cell · doi:10.1016/j.cell.2008.07.001 · Cited by 3,907 · see citing works
New insights into the mechanisms of epithelial–mesenchymal transition and implications for cancer
Dongre, A., & Weinberg, R. A. (2019) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-018-0080-4 · Cited by 3,876 · see citing works
A Cold-Inducible Coactivator of Nuclear Receptors Linked to Adaptive Thermogenesis
Puigserver, P., Wu, Z., Park, C. W., Graves, R., Wright, M., & Spiegelman, B. M. (1998) · Cell · doi:10.1016/s0092-8674(00)81410-5 · Cited by 3,864 · see citing works
Comprehensive molecular characterization of clear cell renal cell carcinoma
The Cancer Genome Atlas Research Network (2013) · Nature · doi:10.1038/nature12222 · Cited by 3,485 · see citing works
TGFβ Signaling in Growth Control, Cancer, and Heritable Disorders
Massagué, J., Blain, S. W., & Lo, R. S. (2000) · Cell · doi:10.1016/s0092-8674(00)00121-5 · Cited by 2,386 · see citing works
HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption
Papandreou, I., Cairns, R. A., Fontana, L., Lim, A. L., & Denko, N. C. (2006) · Cell Metabolism · doi:10.1016/j.cmet.2006.01.012 · Cited by 2,267 · see citing works
Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1.
Semenza, G., Roth, P. H., Fang, H. M., & Wang, G. L. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)31580-6 · Cited by 1,892 · see citing works
Hypoxia, HIF1 and glucose metabolism in the solid tumour
Denko, N. C. (2008) · Nature Reviews Cancer · doi:10.1038/nrc2468 · Cited by 1,707 · see citing works
The Multiple Leiomyoma Consortium (2002) · Nature Genetics · doi:10.1038/ng849 · Cited by 1,635 · see citing works
Kang, H. M., Ahn, S. H., Choi, P., Ko, Y.-A., Han, S. H., Chinga, F., Park, A. S. D., Tao, J., Sharma, K., Pullman, J., et al. (2015) · Nature Medicine · doi:10.1038/nm.3762 · Cited by 1,555 · see citing works
TGFβ signals through a heteromeric protein kinase receptor complex
Wrana, J. L., Attisano, L., Cárcamo, J. M., Zentella‐Dehesa, A., Doody, J. F., Laiho, M., Wang, X.-F., & Massagué, J. (1992) · Cell · doi:10.1016/0092-8674(92)90395-s · Cited by 1,528 · see citing works
LeBleu, V. S., O’Connell, J. T., Herrera, K. N. G., Wikman, H., Pantel, K., Haigis, M. C., de Carvalho, F. M., Damascena, A. S., Chinen, L. T. D., Rocha, R. M., et al. (2014) · Nature Cell Biology · doi:10.1038/ncb3039 · Cited by 1,412 · see citing works
TGFβ signalling: a complex web in cancer progression
Ikushima, H., & Miyazono, K. (2010) · Nature reviews. Cancer · doi:10.1038/nrc2853 · Cited by 1,170 · see citing works
Oncogenic BRAF Regulates Oxidative Metabolism via PGC1α and MITF
Haq, R., Shoag, J., Andreu-Perez, P., Yokoyama, S., Edelman, H., Rowe, G. C., Frederick, D. T., Hurley, A. D., Nellore, A., Kung, A. L., et al. (2013) · Cancer Cell · doi:10.1016/j.ccr.2013.02.003 · Cited by 818 · see citing works
Janzen, N. K., Kim, H. L., Figlin, R. A., et al. (2003) · Urologic Clinics of North America · doi:10.1016/s0094-0143(03)00056-9 · Cited by 784 · see citing works
Crystal Structure of a Smad MH1 Domain Bound to DNA
Shi, Y., Wang, Y., Jayaraman, L., Yang, H., Massagué, J., & Pavletich, N. P. (1998) · Cell · doi:10.1016/s0092-8674(00)81600-1 · Cited by 726 · see citing works
MYC/PGC-1α Balance Determines the Metabolic Phenotype and Plasticity of Pancreatic Cancer Stem Cells
Sancho, P., Burgos-Ramos, E., Tavera, A., Bou Kheir, T., Jagust, P., Schoenhals, M., Barneda, D., Sellers, K., Campos-Olivas, R., Graña, O., et al. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.08.015 · Cited by 722 · see citing works
Binding of the von Hippel-Lindau Tumor Suppressor Protein to Elongin B and C
Kibel, A. S., Iliopoulos, O., DeCaprio, J. A., & Kaelin, W. G. (1995) · Science · doi:10.1126/science.7660130 · Cited by 664 · see citing works
Improved Identification of von Hippel-Lindau Gene Alterations in Clear Cell Renal Tumors
Nickerson, M. L., Jaeger, E., Shi, Y., Durocher, J. A., Mahurkar, S., Zaridze, D. G., Matveev, V. B., Janout, V., Kollárová, H., Bencko, V., et al. (2008) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-07-4921 · Cited by 589 · see citing works
A Smad Transcriptional Corepressor
Wotton, D., Lo, R. S., Lee, S., & Massagué, J. (1999) · Cell · doi:10.1016/s0092-8674(00)80712-6 · Cited by 554 · see citing works
Chen, F., Chandrashekar, D. S., Varambally, S., & Creighton, C. J. (2019) · Nature Communications · doi:10.1038/s41467-019-13528-0 · Cited by 530 · see citing works
Self-citationThe Ski oncoprotein interacts with the Smad proteins to repress TGFbeta signalingPreprint
Luo, K., Stroschein, S. L., Wang, W., Chen, D. Y., Martens, E., Zhou, S., & Zhou, Q. (1999) · Genes & Development · doi:10.1101/gad.13.17.2196 · Cited by 468 · see citing works
Genetic and Functional Studies Implicate <i>HIF1</i> α as a 14q Kidney Cancer Suppressor Gene
Shen, C., Beroukhim, R., Schumacher, S. E., Zhou, J., Chang, M., Signoretti, S., & Kaelin, W. G. (2011) · Cancer Discovery · doi:10.1158/2159-8290.cd-11-0098 · Cited by 413 · see citing works
Acetate Production from Glucose and Coupling to Mitochondrial Metabolism in Mammals
Liu, X., Cooper, D. E., Cluntun, A. A., Warmoes, M. O., Zhao, S., Reid, M. A., Liu, J., Lund, P. J., Lopes, M. D. C., Garcia, B. A., et al. (2018) · Cell · doi:10.1016/j.cell.2018.08.040 · Cited by 408 · see citing works
Self-citationHeterogeneity of tumor-induced gene expression changes in the human metabolic network
Hu, J., Locasale, J. W., Bielas, J. H., O'Sullivan, J., Sheahan, K., Cantley, L. C., Heiden, M. G. V., & Vitkup, D. (2013) · Nature Biotechnology · doi:10.1038/nbt.2530 · Cited by 407 · see citing works
Self-citationAkiyoshi, S., Inoue, H., Hanai, J., Kusanagi, K., Nemoto, N., Miyazono, K., & Kawabata, M. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.49.35269 · Cited by 373 · see citing works
Simonnet, H. (2002) · Carcinogenesis · doi:10.1093/carcin/23.5.759 · Cited by 346 · see citing works
Grubb, R. L., FRANKS, M. E., Toro, J. R., Middelton, L. A., Choyke, L. T., Fowler, S. E., Torres-Cabala, C. A., Glenn, G. M., Choyke, P. L., Merino, M. J., et al. (2007) · The Journal of Urology · doi:10.1016/j.juro.2007.01.155 · Cited by 282 · see citing works
Courtney, K. D., Bezwada, D., Mashimo, T., Pichumani, K., Vemireddy, V., Funk, A. M., Wimberly, J., McNeil, S. S., Kapur, P., Lotan, Y., et al. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.07.020 · Cited by 280 · see citing works
The eukaryotic promoter database in its 30th year: focus on non-vertebrate organisms
Dreos, R., Ambrosini, G., Groux, R., Périer, R. C., & Bücher, P. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkw1069 · Cited by 275 · see citing works
Succinate Dehydrogenase Kidney Cancer: An Aggressive Example of the Warburg Effect in Cancer
Ricketts, C. J., Shuch, B. M., Vocke, C. D., Metwalli, A. R., Bratslavsky, G., Middelton, L. A., Yang, Y., Wei, M.-H., Pautler, S. E., Peterson, J. C., et al. (2012) · The Journal of Urology · doi:10.1016/j.juro.2012.08.030 · Cited by 239 · see citing works
Sudarshan, S., Sourbier, C., Kong, H.-S., Block, K., Romero, V. A. V., Yang, Y., Galindo, C., Mollapour, M., Scroggins, B., Goode, N., et al. (2009) · Molecular and Cellular Biology · doi:10.1128/mcb.00483-09 · Cited by 217 · see citing works
Self-citationThe von Hippel–Lindau protein, HIF hydroxylation, and oxygen sensing
Kaelin, W. G. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.08.165 · Cited by 213 · see citing works
The metabolic co-regulator PGC1α suppresses prostate cancer metastasis
Torrano, V., Valcárcel-Jiménez, L., Cortázar, A. R., Liu, X., Urosevic, J., Castillo-Martín, M., Fernández‐Ruiz, S., Morciano, G., Caro‐Maldonado, A., Guiu, M., et al. (2016) · Nature Cell Biology · doi:10.1038/ncb3357 · Cited by 210 · see citing works
Self-citationA PGC1α-mediated transcriptional axis suppresses melanoma metastasis
Luo, C., Lim, J.-H., Lee, Y., Granter, S. R., Thomas, A., Vázquez, F., Widlund, H. R., & Puigserver, P. (2016) · Nature · doi:10.1038/nature19347 · Cited by 205 · see citing works
Multiple Modes of Repression by the Smad Transcriptional Corepressor TGIF
Wotton, D., Lo, R. S., Swaby, L.-A. C., & Massagué, J. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.52.37105 · Cited by 201 · see citing works
HDAC inhibitors elicit metabolic reprogramming by targeting super-enhancers in glioblastoma models
Nguyen, T. T. T., Zhang, Y., Shang, E., Shu, C., Torrini, C., Zhao, J., Bianchetti, E., Mela, A., Humala, N., Mahajan, A., et al. (2020) · Journal of Clinical Investigation · doi:10.1172/jci129049 · Cited by 201 · see citing works
Suppression of PGC-1α Is Critical for Reprogramming Oxidative Metabolism in Renal Cell Carcinoma
LaGory, E. L., Wu, C., Taniguchi, C. M., Ding, C. C., Chi, J., von Eyben, R., Scott, D. A., Richardson, A. D., & Giaccia, A. J. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.06.006 · Cited by 191 · see citing works
Rodríguez‐García, A., Samsó, P., Fontova, P., Simon‐Molas, H., Manzano, À., Castaño, E., Rosa, J. L., Martinez-Outshoorn, U. E., Ventura, F., Navarro‐Sabaté, À., et al. (2017) · FEBS Journal · doi:10.1111/febs.14201 · Cited by 174 · see citing works
Decrease of mitochondrial DNA content and energy metabolism in renal cell carcinoma
Meierhofer, D. (2004) · Carcinogenesis · doi:10.1093/carcin/bgh104 · Cited by 164 · see citing works
TGIF2 Interacts with Histone Deacetylase 1 and Represses Transcription
Melhuish, T. A., Gallo, C. M., & Wotton, D. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m103377200 · Cited by 137 · see citing works
Liu, M., Quek, L., Sultani, G., & Turner, N. A. (2016) · Cancer & Metabolism · doi:10.1186/s40170-016-0160-x · Cited by 97 · see citing works
Integrative Epigenetic and Gene Expression Analysis of Renal Tumor Progression to Metastasis
Nam, H., Chandrashekar, D. S., Kundu, A., Shelar, S. B., Kho, E.-Y., Sonpavde, G., Naik, G., Ghatalia, P., Livi, C. B., Varambally, S., et al. (2018) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-17-0636 · Cited by 46 · see citing works
Self-citationLi, W., Wei, Z., Liu, Y., et al. (2010) · Neoplasma · doi:10.4149/neo_2010_03_234 · Cited by 43 · see citing works
Kundu, A., Shelar, S. B., Ghosh, A. P., Ballestas, M. E., Kirkman, R. L., Nam, H., Brinkley, G. J., Karki, S., Mobley, J. A., Bae, S., et al. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra119.011089 · Cited by 33 · see citing works
Self-citationPGC1α suppresses kidney cancer progression by inhibiting collagen-induced SNAIL expression
Nam, H., Kundu, A., Brinkley, G. J., Chandrashekar, D. S., Kirkman, R. L., Chakravarthi, B. V. S. K., Orlandella, R. M., Norian, L. A., Sonpavde, G., Ghatalia, P., et al. (2020) · Matrix Biology · doi:10.1016/j.matbio.2020.01.001 · Cited by 25 · see citing works
Self-citationGenomic regression analysis of coordinated expression
Cai, L., Li, Q., Du, Y., Yun, J., Xie, Y., DeBerardinis, R. J., & Xiao, G. (2017) · Nature Communications · doi:10.1038/s41467-017-02181-0 · Cited by 21 · see citing works
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- [35]Cancer Genome Atlas Research Network Comprehensive molecular characterization of clear cell renal cell carcinoma Nature 2013 499 7456 43 49 10.1038/nature12222 23792563 PMC3771322 · DOI · Paper page
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HDACs and the epigenetic plasticity of cancer cells: target the complexity
Brancolini, C., Gagliano, T., & Minisini, M. (2022) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2022.108190 · Cited by 55 · see citing works
- Authors
- Nam, H., Kundu, A., Karki, S., Brinkley, G. J., Chandrashekar, D. S., Kirkman, R. L., Liu, J., Liberti, M. V., Locasale, J. W., Mitchell, T., Varambally, S., & Sudarshan, S.
- Affiliations
- Department of Urology and
- University of Alabama at Birmingham (US)
- Duke University (US)
- Corresponding author
- Sudarshan, Sunil
- ORCID
- Venue
- JCI Insight
- Published
- 2021-11-22
- Volume
- 6
- Issue
- 22
- ISSN
- 2379-3708 (ISSN-L)
- PMC
- PMC8663777
- OpenAlex
- W3202716505
- Cited by
- 36
- References
- 50
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 10 · 2023: 6 · 2022: 4
- FWCI
- 1.98
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- JCI Insight (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- U.S. Department of Veterans Affairs (BX002930)
- NIH/NCI (R01CA20053, P30 CA013148)
- Urology Care Foundation (669279)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- renal cell carcinoma, TGF-beta signaling, HDAC7, TCA cycle enzymes, mitochondrial metabolism, PGC-1α, glucose metabolism, TGF-beta inhibition, tumor growth, metastasis
- MeSH terms
- Animals, Citric Acid Cycle, Histone Deacetylases, Humans, Kidney Neoplasms, Transfection, Transforming Growth Factor beta, Gene Expression Profiling, Mice
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