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Recent genome-wide transcriptomic and epigenomic profiling of clear cell renal cell carcinoma (ccRCC) by The Cancer Genome Atlas (TCGA) identified <jats:italic>UQCRH<\/jats:italic> 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.<\/jats:p>","DOI":"10.1038\/s41598-020-72107-2","type":"journal-article","created":{"date-parts":[[2020,9,14]],"date-time":"2020-09-14T10:03:01Z","timestamp":1600077781000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["UQCRH downregulation promotes Warburg effect in renal cell carcinoma cells"],"prefix":"10.1038","volume":"10","author":[{"given":"Yanting","family":"Luo","sequence":"first","affiliation":[]},{"given":"Louise","family":"Medina Bengtsson","sequence":"additional","affiliation":[]},{"given":"Xuechun","family":"Wang","sequence":"additional","affiliation":[]},{"given":"Tianhe","family":"Huang","sequence":"additional","affiliation":[]},{"given":"Guoqiang","family":"Liu","sequence":"additional","affiliation":[]},{"given":"Sean","family":"Murphy","sequence":"additional","affiliation":[]},{"given":"Caiqin","family":"Wang","sequence":"additional","affiliation":[]},{"suffix":"III","given":"John","family":"Koren","sequence":"additional","affiliation":[]},{"given":"Zachary","family":"Schafer","sequence":"additional","affiliation":[]},{"given":"Xin","family":"Lu","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2020,9,14]]},"reference":[{"key":"72107_CR1","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","volume":"144","author":"D Hanahan","year":"2011","unstructured":"Hanahan, D. & Weinberg, R. 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