Histone demethylase JARID1C inactivation triggers genomic instability in sporadic renal cancer

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

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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 HP1á, 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.

Original languageEnglish
Pages (from-to)4625-4637
Number of pages13
JournalJournal of Clinical Investigation
Volume125
Issue number12
DOIs
Publication statusPublished - Dec 1 2015

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Histone Demethylases
Heterochromatin
Kidney Neoplasms
Genomic Instability
Renal Cell Carcinoma
Adaptor Protein Complex 4
Neoplasms
Histone Code
Cullin Proteins
Untranslated RNA
Mutation
Chromatin Assembly and Disassembly
Lysine
Chromatin
Proteins
Genome

ASJC Scopus subject areas

  • Medicine(all)

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Histone demethylase JARID1C inactivation triggers genomic instability in sporadic renal cancer. / Rondinelli, Beatrice; Rosano, Dalia; Antonini, Elena; Frenquelli, Michela; Montanini, Laura; Huang, Dachuan; Segalla, Simona; Yoshihara, Kosuke; Amin, Samir B.; Lazarevic, Dejan; Tean, Bin; Verhaak, Roel G W; Andrew Futreal, P.; Di Croce, Luciano; Chin, Lynda; Cittaro, Davide; Tonon, Giovanni.

In: Journal of Clinical Investigation, Vol. 125, No. 12, 01.12.2015, p. 4625-4637.

Research output: Contribution to journalArticle

Rondinelli, B, Rosano, D, Antonini, E, Frenquelli, M, Montanini, L, Huang, D, Segalla, S, Yoshihara, K, Amin, SB, Lazarevic, D, Tean, B, Verhaak, RGW, Andrew Futreal, P, Di Croce, L, Chin, L, Cittaro, D & Tonon, G 2015, 'Histone demethylase JARID1C inactivation triggers genomic instability in sporadic renal cancer', Journal of Clinical Investigation, vol. 125, no. 12, pp. 4625-4637. https://doi.org/10.1172/JCI81040
Rondinelli B, Rosano D, Antonini E, Frenquelli M, Montanini L, Huang D et al. Histone demethylase JARID1C inactivation triggers genomic instability in sporadic renal cancer. Journal of Clinical Investigation. 2015 Dec 1;125(12):4625-4637. https://doi.org/10.1172/JCI81040
Rondinelli, Beatrice ; Rosano, Dalia ; Antonini, Elena ; Frenquelli, Michela ; Montanini, Laura ; Huang, Dachuan ; Segalla, Simona ; Yoshihara, Kosuke ; Amin, Samir B. ; Lazarevic, Dejan ; Tean, Bin ; Verhaak, Roel G W ; Andrew Futreal, P. ; Di Croce, Luciano ; Chin, Lynda ; Cittaro, Davide ; Tonon, Giovanni. / Histone demethylase JARID1C inactivation triggers genomic instability in sporadic renal cancer. In: Journal of Clinical Investigation. 2015 ; Vol. 125, No. 12. pp. 4625-4637.
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AU - Montanini, Laura

AU - Huang, Dachuan

AU - Segalla, Simona

AU - Yoshihara, Kosuke

AU - Amin, Samir B.

AU - Lazarevic, Dejan

AU - Tean, Bin

AU - Verhaak, Roel G W

AU - Andrew Futreal, P.

AU - Di Croce, Luciano

AU - Chin, Lynda

AU - Cittaro, Davide

AU - Tonon, Giovanni

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N2 - 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 HP1á, 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.

AB - 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 HP1á, 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.

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