Abstract
Ubiquinol-cytochrome c reductase hinge protein (UQCRH) is the hinge protein for the multi-subunit complex III of the mitochondrial electron transport chain and is involved in the electron transfer reaction between cytochrome c1 and c. Recent genome-wide transcriptomic and epigenomic profiling of clear cell renal cell carcinoma (ccRCC) by The Cancer Genome Atlas (TCGA) identified UQCRH as the top-ranked gene showing inverse correlation between DNA hypermethylation and mRNA downregulation. The function and underlying mechanism of UQCRH in the Warburg effect metabolism of ccRCC have not been characterized. Here, we verified the clinical association of low UQCRH expression and shorter survival of ccRCC patients through in silico analysis and identified KMRC2 as a highly relevant ccRCC cell line that displays hypermethylation-induced UQCRH extinction. Ectopic overexpression of UQCRH in KMRC2 restored mitochondrial membrane potential, increased oxygen consumption, and attenuated the Warburg effect at the cellular level. UQCRH overexpression in KMRC2 induced higher apoptosis and slowed down in vitro and in vivo tumor growth. UQCRH knockout by CRISPR/Cas9 had little impact on the metabolism and proliferation of 786O ccRCC cell line, suggesting the dispensable role of UQCRH in cells that have entered a Warburg-like state through other mechanisms. Together, our study suggests that loss of UQCRH expression by hypermethylation may promote kidney carcinogenesis through exacerbating the functional decline of mitochondria thus reinforcing the Warburg effect.
Highlights
Metabolic reprograming is a crucial hallmark of c ancer[1] and is revealing in clear cell renal cell carcinoma2–4. ccRCC is the most common (∼ 75%), lethal subtype of kidney cancer
To examine the expression pattern of ubiquinol-cytochrome c reductase hinge protein (UQCRH) in cancers, we surveyed the The Cancer Genome Atlas (TCGA) data using two computational tools, TIMER and GEPIA, and observed that ccRCC was the only cancer type among various TCGA cancer types that showed significantly lower mRNA level of UQCRH in tumors compared with normal tissues (Fig. 1a, b)
In the TCGA ccRCC cohort, UQCRH promoter region was significantly hypermethylated (Fig. 1d), and the methylation was inversely correlated with mRNA expression (Fig. 1e)
Summary
Metabolic reprograming is a crucial hallmark of c ancer[1] and is revealing in clear cell renal cell carcinoma (ccRCC)2–4. ccRCC is the most common (∼ 75%), lethal subtype of kidney cancer. HIF-2α have opposing activity in ccRCC with HIF-2α playing the dominant tumor-promoting r ole[10,11,12], it remains unclear if the VHL-HIF axis is sufficient to explain the downregulated mitochondrial function in ccRCC. New insights are emerging from the recent TCGA (The Cancer Genome Atlas) study of ccRCC, which identified ubiquinol-cytochrome c reductase hinge protein (UQCRH) as the top-ranked gene with profound promoter hypermethylation and inverse correlation with the mRNA level[5]. The recent Clinical Proteomics Tumor Analysis Consortium (CPTAC) study on ccRCC further identified that UQCRH is among the 565 significantly downregulated proteins in ccRCC tumors relative to normal adjacent tissues[6]. UQCRH is an integral subunit (the hinge protein) of the 11-subunit complex III (the ubiquinol:cytochrome c oxidoreductase) of the electron transport chain (ETC) in the mitochondrion. We found that overexpression of UQCRH in KMRC2 reprogrammed the metabolic activity at several levels and demonstrated the metabolically-linked tumor suppressive activity of UQCRH in at least some of the ccRCC cases
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