title: Histone demethylase JARID1C inactivation triggers genomic instability in sporadic renal cancer.
abstract: Mutations in genes encoding chromatin-remodeling proteins are often identified in a variety of cancers. For example, the histone demethylase JARID1C is frequently inactivated in patients with clear cell renal cell carcinoma (ccRCC); however, it is largely unknown how JARID1C dysfunction promotes cancer. Here, we determined that JARID1C binds broadly to chromatin domains characterized by the trimethylation of lysine 9 (H3K9me3), which is a histone mark enriched in heterochromatin. Moreover, we found that JARID1C localizes on heterochromatin, is required for heterochromatin replication, and forms a complex with established players of heterochromatin assembly, including SUV39H1 and HP1α, as well as with proteins not previously associated with heterochromatin assembly, such as the cullin 4 (CUL4) complex adaptor protein DDB1. Transcription on heterochromatin is tightly suppressed to safeguard the genome, and in ccRCC cells, JARID1C inactivation led to the unrestrained expression of heterochromatic noncoding RNAs (ncRNAs) that in turn triggered genomic instability. Moreover, ccRCC patients harboring JARID1C mutations exhibited aberrant ncRNA expression and increased genomic rearrangements compared with ccRCC patients with tumors endowed with other genetic lesions. Together, these data suggest that inactivation of JARID1C in renal cancer leads to heterochromatin disruption, genomic rearrangement, and aggressive ccRCCs. Moreover, our results shed light on a mechanism that underlies genomic instability in sporadic cancers.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Rondinelli
authors.forename: Dalia
authors.initials: D
authors.lastname: Rosano
authors.forename: Elena
authors.initials: E
authors.lastname: Antonini
authors.forename: Michela
authors.initials: M
authors.lastname: Frenquelli
authors.forename: Laura
authors.initials: L
authors.lastname: Montanini
authors.forename: DaChuan
authors.initials: D
authors.lastname: Huang
authors.forename: Simona
authors.initials: S
authors.lastname: Segalla
authors.forename: Kosuke
authors.initials: K
authors.lastname: Yoshihara
authors.forename: Samir B
authors.initials: SB
authors.lastname: Amin
authors.forename: Dejan
authors.initials: D
authors.lastname: Lazarevic
authors.forename: Bin Tean
authors.initials: BT
authors.lastname: The
authors.forename: Roel G W
authors.initials: RG
authors.lastname: Verhaak
authors.forename: P Andrew
authors.initials: PA
authors.lastname: Futreal
authors.forename: Luciano
authors.initials: L
authors.lastname: Di Croce
authors.forename: Lynda
authors.initials: L
authors.lastname: Chin
authors.forename: Davide
authors.initials: D
authors.lastname: Cittaro
authors.forename: Giovanni
authors.initials: G
authors.lastname: Tonon
mesh_terms: D000818:Animals; D002292:Carcinoma, Renal Cell / Q000201:enzymology* / Q000235:genetics; D000090266:Chromobox Protein Homolog 5; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D042822:Genomic Instability; D006367:HeLa Cells; D006570:Heterochromatin / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D056466:Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007680:Kidney Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008745:Methylation; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009154:Mutation; D041681:NIH 3T3 Cells; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C000715594:CBX5 protein, human; C091435:DDB1 protein, human; D004268:DNA-Binding Proteins; C490415:Ddb1 protein, mouse; D006570:Heterochromatin; D006657:Histones; D009363:Neoplasm Proteins; D012097:Repressor Proteins; D000090266:Chromobox Protein Homolog 5; D056466:Histone Demethylases; C086877:KDM5C protein, human; C490173:Kdm5c protein, mouse; D010089:Oxidoreductases, N-Demethylating; C407843:SUV39H1 protein, human; C498700:Suv39h1 protein, mouse; D008780:Methyltransferases