The Complex Interplay between Metabolic Reprogramming and Epigenetic Alterations in Renal Cell Carcinoma

Renal cell carcinoma (RCC) is the most common malignancy affecting the kidney. Current therapies are mostly curative for localized disease, but do not completely preclude recurrence and metastization. Thus, it is imperative to develop new therapeutic strategies based on RCC biological properties. Presently, metabolic reprograming and epigenetic alterations are recognized cancer hallmarks and their interactions are still in its infancy concerning RCC. In this review, we explore RCC biology, highlighting genetic and epigenetic alterations that contribute to metabolic deregulation of tumor cells, including high glycolytic phenotype (Warburg effect). Moreover, we critically discuss available data concerning epigenetic enzymes’ regulation by aberrant metabolite accumulation and their consequences in RCC emergence and progression. Finally, we emphasize the clinical relevance of uncovering novel therapeutic targets based on epigenetic reprograming by metabolic features to improve treatment and survival of RCC patients.

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Genetic and Epigenetic Alterations in Renal Cell Carcinoma

Genitourinary Pathology ◽

10.1007/978-1-4939-2044-0_32 ◽

2015 ◽

pp. 407-415

Author(s):

Fang-Ming Deng ◽

Ming Zhou

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Epigenetic Alterations

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Stereotactic ablative radiation therapy in renal cell carcinoma: From oligometastatic to localized disease

Critical Reviews in Oncology/Hematology ◽

10.1016/j.critrevonc.2017.07.004 ◽

2017 ◽

Vol 117 ◽

pp. 48-56 ◽

Cited By ~ 9

Author(s):

Filippo Alongi ◽

Stefano Arcangeli ◽

Luca Triggiani ◽

Rosario Mazzola ◽

Michela Buglione di Monale e Bastia ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Radiation Therapy ◽

Cell Carcinoma ◽

Renal Cell ◽

Localized Disease ◽

Stereotactic Ablative Radiation Therapy

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Extracellular Vesicles Enriched in hsa-miR-301a-3p and hsa-miR-1293 Dynamics in Clear Cell Renal Cell Carcinoma Patients: Potential Biomarkers of Metastatic Disease

Cancers ◽

10.3390/cancers12061450 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1450 ◽

Cited By ~ 2

Author(s):

Francisca Dias ◽

Ana Luísa Teixeira ◽

Inês Nogueira ◽

Mariana Morais ◽

Joana Maia ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Metastatic Disease ◽

Renal Cell ◽

Clear Cell ◽

Epigenetic Mechanism ◽

Mirna Profile ◽

Cell Renal Cell Carcinoma ◽

Localized Disease ◽

Potential Biomarkers

Clear cell renal cell carcinoma (ccRCC) is the most aggressive subtype of kidney cancer and up to 40% of patients submitted to surgery with a curative intent will relapse. Thus, the aim of this study was to analyze the applicability of an Extracellular vesicle (EV) derived miRNA profile as potential prognosis biomarkers in ccRCC patients. We analyzed a nine-miRNA profile in plasma EVs from 32 ccRCC patients with localized disease (before and after surgery) and in 37 patients with metastatic disease. We observed that the levels of EV-derived hsa-miR-25-3p, hsa-miR-126-5p, hsa-miR-200c-3p, and hsa-miR-301a-3p decreased after surgery, whereas hsa-miR-1293 EV-levels increased. Furthermore, metastatic patients presented higher levels of hsa-miR-301a-3p and lower levels of hsa-miR-1293 when compared to patients with localized disease after surgery. Functional enrichment analysis of the targets of the four miRNAs that decreased after surgery resulted in an enrichment of terms related to cell cycle, proliferation, and metabolism, suggesting that EV-miRNA enrichment in the presence of the tumor could represent an epigenetic mechanism to sustain tumor development. Taken together, these results suggest that EVs content varies depending on the presence or absence of the disease and that an increase of EV-derived hsa-miR-301a-3p, and decrease of EV-derived hsa-miR-1293, may be potential biomarkers of metastatic ccRCC.

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Metabolic reprogramming and epigenetic landscape: an interplay to renal cell carcinoma aggressiveness promotion

European Urology Supplements ◽

10.1016/s1569-9056(19)33292-0 ◽

2019 ◽

Vol 18 (8) ◽

pp. e3042

Author(s):

V. Miranda-Gonçalves ◽

A. Lameirinhas ◽

A. Pereira-Pinto ◽

A. Macedo-Silva ◽

A. Pires-Luis ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Metabolic Reprogramming ◽

Epigenetic Landscape

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The m6A RNA demethylase FTO is a HIF-independent synthetic lethal partner with the VHL tumor suppressor

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2000516117 ◽

2020 ◽

Vol 117 (35) ◽

pp. 21441-21449 ◽

Cited By ~ 1

Author(s):

Yiren Xiao ◽

Kaushik N. Thakkar ◽

Hongjuan Zhao ◽

James Broughton ◽

Yang Li ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Tumor Suppressor ◽

Cell Carcinoma ◽

Renal Cell ◽

Metabolic Reprogramming ◽

Integrated Analysis ◽

Antiangiogenic Agents ◽

Synthetic Lethal

Loss of the von Hippel–Lindau (VHL) tumor suppressor is a hallmark feature of renal clear cell carcinoma. VHL inactivation results in the constitutive activation of the hypoxia-inducible factors (HIFs) HIF-1 and HIF-2 and their downstream targets, including the proangiogenic factors VEGF and PDGF. However, antiangiogenic agents and HIF-2 inhibitors have limited efficacy in cancer therapy due to the development of resistance. Here we employed an innovative computational platform, Mining of Synthetic Lethals (MiSL), to identify synthetic lethal interactions with the loss of VHL through analysis of primary tumor genomic and transcriptomic data. Using this approach, we identified a synthetic lethal interaction between VHL and the m6A RNA demethylase FTO in renal cell carcinoma. MiSL identified FTO as a synthetic lethal partner of VHL because deletions of FTO are mutually exclusive with VHL loss in pan cancer datasets. Moreover, FTO expression is increased in VHL-deficient ccRCC tumors compared to normal adjacent tissue. Genetic inactivation of FTO using multiple orthogonal approaches revealed that FTO inhibition selectively reduces the growth and survival of VHL-deficient cells in vitro and in vivo. Notably, FTO inhibition reduced the survival of both HIF wild type and HIF-deficient tumors, identifying FTO as an HIF-independent vulnerability of VHL-deficient cancers. Integrated analysis of transcriptome-wide m6A-seq and mRNA-seq analysis identified the glutamine transporter SLC1A5 as an FTO target that promotes metabolic reprogramming and survival of VHL-deficient ccRCC cells. These findings identify FTO as a potential HIF-independent therapeutic target for the treatment of VHL-deficient renal cell carcinoma.

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