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; Verhaak, Roel G.W.; Futreal, P. Andrew; Croce, Luciano Di; Chin, Lynda; Cittaro, Davide; Tonon, Giovanni

doi:10.1172/jci81040

Cited by 63 publications

(60 citation statements)

References 85 publications

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“…Here JARID1B was enriched at DNA damage sites, where it was required for recruiting Ku70 and BRCA1 during non-homologous end joining [67]. Similar findings have also implicated JARID1C in enforcing genomic stability in sporadic renal cancer [68]. …”

Section: Jarid1 Contribution To Cancer Progressionmentioning

confidence: 82%

JARID1 Histone Demethylases: Emerging Targets in Cancer

et al. 2017

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JARID1 proteins are histone demethylases that both regulate normal cell fates during development and contribute to the epigenetic plasticity that underlies malignant transformation. This H3K4 demethylase family participates in multiple repressive transcriptional complexes at promoters and has broader regulatory effects on chromatin that remain ill-defined. There is growing understanding of the oncogenic and tumor suppressive functions of JARID1 proteins, which are contingent on cell context and the protein isoform. Their contributions to stem cell-like de-differentiation, tumor aggressiveness, and therapy resistance in cancer have sustained interest in the development of JARID1 inhibitors. Here we review the diverse and context-specific functions of the JARID1 proteins that may impact the utilization of emerging targeted inhibitors of this histone demethylase family in cancer therapy.

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Section: Jarid1 Contribution To Cancer Progressionmentioning

confidence: 82%

JARID1 Histone Demethylases: Emerging Targets in Cancer

et al. 2017

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“…Furthermore, it has been shown that knockdown of KDM5D through RNA-interference (RNAi) increases cell proliferation and reduces apoptosis in prostate cancer19, suggesting a tumor suppressor function for this gene. Intriguingly, KDM5C , the X-linked homologue of KDM5D is recurrently mutated in ccRCC8912, and its inactivation leads to genomic instability in ccRCC through deregulation of H3K4 methylation20. KDM5D shows 85% sequence identity to KDM5C, and the products of these two genes possess a similar function in demethylating tri-methyl H3K41820.…”

Section: Resultsmentioning

confidence: 99%

“…Intriguingly, KDM5C , the X-linked homologue of KDM5D is recurrently mutated in ccRCC8912, and its inactivation leads to genomic instability in ccRCC through deregulation of H3K4 methylation20. KDM5D shows 85% sequence identity to KDM5C, and the products of these two genes possess a similar function in demethylating tri-methyl H3K41820. Given this functional similarity, we surveyed the mutational status of KDM5C in our discovery set, and investigated possible relationships between mutational status of KDM5C and KDM5D in tumors of male patients.…”

Section: Resultsmentioning

confidence: 99%

“…Given the reported tumor-suppressive function of KDM5D in prostate cancer19, and of its X-link homolog KDM5C in renal cancer20, we set out to examine whether KDM5D expression has an anti-tumor activity in renal cancer. We first evaluated KDM5D expression levels in several renal cancer cell lines, which have been derived from tumors resected from male patients.…”

Section: Resultsmentioning

confidence: 99%

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Loss of chromosome Y leads to down regulation of KDM5D and KDM6C epigenetic modifiers in clear cell renal cell carcinoma

Arseneault

Monlong

Vasudev

et al. 2017

Sci Rep

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Recent genomic studies of sporadic clear cell renal cell carcinoma (ccRCC) have uncovered novel driver genes and pathways. Given the unequal incidence rates among men and women (male:female incidence ratio approaches 2:1), we compared the genome-wide distribution of the chromosomal abnormalities in both sexes. We observed a higher frequency for the somatic recurrent chromosomal copy number variations (CNVs) of autosomes in male subjects, whereas somatic loss of chromosome X was detected exclusively in female patients (17.1%). Furthermore, somatic loss of chromosome Y (LOY) was detected in about 40% of male subjects, while mosaic LOY was detected in DNA isolated from peripheral blood in 9.6% of them, and was the only recurrent CNV in constitutional DNA samples. LOY in constitutional DNA, but not in tumor DNA was associated with older age. Amongst Y-linked genes that were downregulated due to LOY, KDM5D and KDM6C epigenetic modifiers have functionally-similar X-linked homologs whose deficiency is involved in ccRCC progression. Our findings establish somatic LOY as a highly recurrent genetic defect in ccRCC that leads to downregulation of hitherto unsuspected epigenetic factors, and suggest that different mechanisms may underlie the somatic and mosaic LOY observed in tumors and peripheral blood, respectively.

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“…Thus, such epigenetic difference provides the rationale to test KDM6A inhibitor in the epigenetic therapy of T-ALL patients. H3K4me can be removed by histone demethylases like KDM5C/JARID1C (for H3K4me2/3) [24] and KDM1A/LSD1 (for H3K4me1/2) [45]. In acute myeloid leukemia, LSD1 inhibitor increased H3K4me2 genome wide and enhanced the efficacy of all trans retinoic acid (ATRA)-based treatment of the nonacute promyelocytic leukemia subtype, which is resistant to ATRA treatment alone [45].…”

Section: P300mentioning

confidence: 99%

ChIP-seq in Studying Epigenetic Mechanisms of Disease and Promoting Precision Medicine: Progresses and Future Directions

et al. 2016

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Chromatin immunoprecipitation followed by sequencing (ChIP-seq) is widely used for mapping histone modifications, histone proteins, chromatin regulators, transcription factors and other DNA-binding proteins. It has played a significant role in our understanding of disease mechanisms and in exploring epigenetic changes for potential clinical applications. However, the conventional protocol requires large amounts of starting material and does not quantify the actual occupancy, limiting its applications in clinical settings. Herein we summarize the latest progresses in utilizing ChIP-seq to link epigenetic alterations to disease initiation and progression, and the implications in precision medicine. We provide an update on the newly developed ChIP-seq protocols, especially those suitable for scare clinical samples. Technical and analytical challenges are outlined together with recommendations for improvement. Finally, future directions in expediting ChIP-seq use in clinic are discussed.

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Histone demethylase JARID1C inactivation triggers genomic instability in sporadic renal cancer

Cited by 63 publications

References 85 publications

JARID1 Histone Demethylases: Emerging Targets in Cancer

JARID1 Histone Demethylases: Emerging Targets in Cancer

Loss of chromosome Y leads to down regulation of KDM5D and KDM6C epigenetic modifiers in clear cell renal cell carcinoma

ChIP-seq in Studying Epigenetic Mechanisms of Disease and Promoting Precision Medicine: Progresses and Future Directions

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