Histone demethylase JARID1C inactivation triggers genomic instability in sporadic renal cancer
Beatrice Rondinelli, … , Davide Cittaro, Giovanni Tonon
Beatrice Rondinelli, … , Davide Cittaro, Giovanni Tonon
Published November 9, 2015
Citation Information: J Clin Invest. 2015;125(12):4625-4637. https://doi.org/10.1172/JCI81040.
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Research Article Genetics Oncology

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

Beatrice Rondinelli, Dalia Rosano, Elena Antonini, Michela Frenquelli, Laura Montanini, DaChuan Huang, Simona Segalla, Kosuke Yoshihara, Samir B. Amin, Dejan Lazarevic, Bin Tean The, Roel G.W. Verhaak, P. Andrew Futreal, Luciano Di Croce, Lynda Chin, Davide Cittaro, Giovanni Tonon

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Figure 6

JARID1C-inactivating mutations cause derepression through aberrant heterochromatic transcription, enhanced genomic rearrangements, and poor prognosis in ccRCC patients.

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JARID1C-inactivating mutations cause derepression through aberrant heter...
(A) Volcano plot shows a comparison of DNA methylation for JARID1C-mutated versus unmutated tumors (n = 292) (HumanMethylation450 platform; Illumina). Above the dashed line are indicated CpG loci with a Benjamini-Hochberg (BH) FDR of less than 0.05. Points are colored according to the FDR value. (B) Heatmap showing CpG loci with JARID1C mutation–associated (J1C mut) DNA methylation (CpG loci with an FDR <0.05, above the dashed line in the volcano plot); blue to red indicates low to high DNA methylation. The loci are split into those hypermethylated (top split, n = 105) or hypomethylated (bottom split, n = 267) in JARID1C mutants (left split) versus ccRCC WT for JARID1C (right split). The middle split shows the methylation status of 16 normal kidney samples (N). (C) Expression of human SAT2 assayed by qPCR on 9 J1C-mutated primary ccRCCs (see Supplemental Table 1 for sample information). Expression of tumor and matched normal tissue. Results are expressed relative to RPLPO and are presented as the mean ± SEM. P < 0.05, Wilcoxon matched-pairs signed-rank test. (D) Tumors from patients with JARID1C mutations showed an increased number of CNAs (x axis corresponds to the fraction of the copy number–altered genome; y axis corresponds to the frequency in patients). Data shown are from patients with JARID1C mutations, SETD2 mutations, and from ccRCC samples without SETD2 or JARID1C mutations. P < 0.05, χ2 test over the distribution. (E) Kaplan-Meier survival curves comparing patients harboring WT with those harboring mutated JARID1C. Data were derived from TCGA (analyzed through http://www.cbioportal.org). P = 0.05, log-rank significance test. The results shown in this figure are partly based on data generated by TCGA Research Network (http://cancergenome.nih.gov/).