Histone demethylase JARID1C inactivation triggers genomic instability in sporadic renal cancer

Mutations in genes encoding chromatin-remodelingproteins are often identified in a variety of cancers. For example, the histone demethylaseJARID1C 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 heterochromatinreplication, and forms a complex with established players of heterochromatinassembly, including SUV39H1and HP1α, as well as with proteins not previously associated with heterochromatinassembly, such as the cullin4 (CUL4) complex adaptor protein DDB1. Transcription on heterochromatinis 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 heterochromatindisruption, genomic rearrangement, and aggressive ccRCCs. Moreover, our results shed light on a mechanism that underlies genomic instabilityin sporadic cancers.