Histone demethylase JARID1C inactivation triggers genomic instability in sporadic renal cancer

Abstract

At the request of the corresponding author, the JCI is retracting this article. The authors were recently made aware of duplicated bands in Figures 1B, 3C, and 4C. After an extensive internal review, it was discovered that these duplications were introduced during figure assembly. The authors have stated that experimental data generated in the lab from the same time period support the original conclusions of the study and that other studies have subsequently confirmed and extended the primary conclusions of the manuscript. However, in the interest of maintaining accuracy in the published scientific literature and because the initial figures were not up to the standards of the JCI,

Genomic profiling reveals mutational landscape in parathyroid carcinomas

“…We observed frequent mutations in genes that directly regulate chromatin structure, including truncating mutations in a recently discovered tumor suppressor, ARID2, implicated in hepatocellular carcinomas and melanomas (36)(37)(38); a missense mutation (p.L1549V in PC09T; dbNSFP radial SVM score = -0.83, 54th percentile) in a histone demethylase KDM5C (also known as JARID1C) that is mutated in 9% of clear cell renal cell carcinomas and its inactivation triggers genomic instability (39). In addition to ARID2 and KDM5C, there are several other chromatin remodeling genes that are not included in the Cancer Gene Census but are mutated in our discovery cohort: a frameshift indel (p.K512fs) in another ARID family gene ARID4A in PC04T; missense mutations or inframe indel in 3 other histone demethylases (KDM4C, p.R919K in PC18T; KDM4E, p.R100H in PC04T; JMJD1C, p.K593_S601del in PC04T); a missense mutation (p.S1128L in PC02T) in the SET domain histone methyltransferase SETD1B that is frequently mutated in gastric and colorectal cancers (40).…”

KDM5 demethylases and their role in cancer cell chemoresistance

“…KDM5C binds to H3K9me3 heterochromatic chromatin domains and is required for heterochromatin replication in a complex with SUV39H1 and HP1α, as well as with the cullin‐4 complex adaptor protein DDB1. Loss of KDM5C discharges the expression of heterochromatic noncoding RNAs, followed by increased genomic instability, that is considered as a negative prognostic marker in clear cell renal carcinoma (ccRCC) . KDM5C mutations have been reported in up to 9% of patients with ccRCC .…”

“…Loss of KDM5D with increased H3K4me3 levels in the promoter regions of relevant genes leads to the development of metastasis . Given the reported tumor‐suppressive function of KDM5D in prostate cancer, and of its X‐link homolog KDM5C in renal cancer (RCC), Arseneault et al . set out to examine whether the KDM5D expression has a tumor protective activity in RCC.…”

Lysine-Specific Histone Demethylases Contribute to Cellular Differentiation and Carcinogenesis

“…KDM5C localizes in heterochromatin, leading to the demethylation of H3K4me3 and enhancing the deposition of H3K9me3 on chromocenters by SUV39H1. When KDM5C is mutated, an increased expression of heterochromatic noncoding RNAs (ncRNAs) triggers genomic instability, leading to clear cell renal cell carcinoma (ccRCC) [141].…”