Loss of the retinoblastoma binding protein 2 (RBP2) histone demethylase suppresses tumorigenesis in mice lacking<i>Rb1</i>or<i>Men1</i>

Lin, Wenchu; Cao, Jian; Liu, Jiayun; Beshiri, Michael L.; Fujiwara, Yuko; Francis, Joshua M.; Cherniack, Andrew D.; Geisen, Christoph; Blair, Lauren P.; Zou, Mike R.; Shen, Xiaohua; Kawamori, Dan; Liu, Zongzhi; Grisanzio, Chiara; Watanabe, Hideo; Minamishima, Yoji Andrew; Zhang, Qing; Kulkarni, Rohit; Signoretti, Sabina; Rodig, Scott J.; Bronson, Roderick T.; Orkin, Stuart H.; Tuck, David; Benevolenskaya, Elizaveta V.; Meyerson, Matthew; Kaelin, William G.; Yan, Qin

doi:10.1073/pnas.1110104108

Cited by 142 publications

(155 citation statements)

References 69 publications

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“…In estrogen receptornegative breast cancers, KDM5A mediates metastatic spread to the lung (31). Consistent with an oncogenic role, genetic ablation of kdm5a delays tumor onset in retinoblastoma mutant mice (32).…”

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confidence: 86%

Characterization of a Linked Jumonji Domain of the KDM5/JARID1 Family of Histone H3 Lysine 4 Demethylases

Horton¹,

Engstrom²,

Zoeller³

et al. 2016

Journal of Biological Chemistry

165

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The KDM5/JARID1 family of Fe(II)-and ␣-ketoglutarate-dependent demethylases remove methyl groups from tri-and dimethylated lysine 4 of histone H3. Accumulating evidence from primary tumors and model systems supports a role for KDM5A (JARID1A/RBP2) and KDM5B (JARID1B/PLU1) as oncogenic drivers. The KDM5 family is unique among the Jumonji domain-containing histone demethylases in that there is an atypical insertion of a DNA-binding ARID domain and a histone-binding PHD domain into the Jumonji domain, which separates the catalytic domain into two fragments (JmjN and JmjC). Here we demonstrate that internal deletion of the ARID and PHD1 domains has a negligible effect on in vitro enzymatic kinetics of the KDM5 family of enzymes. We present a crystal structure of the linked JmjN-JmjC domain from KDM5A, which reveals that the linked domain fully reconstitutes the cofactor (metal ion and ␣-ketoglutarate) binding characteristics of other structurally characterized Jumonji domain demethylases. Docking studies with GSK-J1, a selective inhibitor of the KDM6/ KDM5 subfamilies, identify critical residues for binding of the inhibitor to the reconstituted KDM5 Jumonji domain. Further, we found that GSK-J1 inhibited the demethylase activity of KDM5C with 8.5-fold increased potency compared with that of KDM5B at 1 mM ␣-ketoglutarate. In contrast, JIB-04 (a paninhibitor of the Jumonji demethylase superfamily) had the opposite effect and was ϳ8-fold more potent against KDM5B than against KDM5C. Interestingly, the relative selectivity of JIB-04 toward KDM5B over KDM5C in vitro translates to a ϳ10 -50-fold greater growth-inhibitory activity against breast cancer cell lines. These data define the minimal requirements for enzymatic activity of the KDM5 family to be the linked JmjNJmjC domain coupled with the immediate C-terminal helical zinc-binding domain and provide structural characterization of the linked JmjN-JmjC domain for the KDM5 family, which should prove useful in the design of KDM5 demethylase inhibitors with improved potency and selectivity.

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confidence: 86%

Characterization of a Linked Jumonji Domain of the KDM5/JARID1 Family of Histone H3 Lysine 4 Demethylases

Horton¹,

Engstrom²,

Zoeller³

et al. 2016

Journal of Biological Chemistry

165

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“…GiTools were used for enrichment analysis and heatmap generation (32). Expression data in differentiating Kdm5a f/f and Kdm5a −/− ES cells were taken from one of our other studies (4). Expression data in ES cells from C57BL/6 mouse were used from the Gene Expression Omnibus (GEO) dataset GSE5914.…”

Section: Methodsmentioning

confidence: 99%

“…Kdm5a f/f (wild-type KDM5A) ES cells were isolated from mouse blastocysts of Kdm5a f/f mice, which were maintained on a pure C57BL/6 background. Successful Cre-dependent recombination was performed as previously described (4). ChIP-seq experiments were performed with the KDM5A antibody 1416 following the previously described procedure (28).…”

Section: Methodsmentioning

confidence: 99%

Coordinated repression of cell cycle genes by KDM5A and E2F4 during differentiation

Beshiri

Holmes

Richter

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Epigenetic regulation underlies the robust changes in gene expression that occur during development. How precisely epigenetic enzymes contribute to development and differentiation processes is largely unclear. Here we show that one of the enzymes that removes the activating epigenetic mark of trimethylated lysine 4 on histone H3, lysine (K)-specific demethylase 5A (KDM5A), reinforces the effects of the retinoblastoma (RB) family of transcriptional repressors on differentiation. Global location analysis showed that KDM5A cooccupies a substantial portion of target genes with the E2F4 transcription factor. During ES cell differentiation, knockout of KDM5A resulted in derepression of multiple genomic loci that are targets of KDM5A, denoting a direct regulatory function. In terminally differentiated cells, common KDM5A and E2F4 gene targets were bound by the pRB-related protein p130, a DREAM complex component. KDM5A was recruited to the transcription start site regions independently of E2F4; however, it cooperated with E2F4 to promote a state of deepened repression at cell cycle genes during differentiation. These findings reveal a critical role of H3K4 demethylation by KDM5A in the transcriptional silencing of genes that are suppressed by RB family members in differentiated cells.chromatin | histone demethylase | whole-genome sequencing | histone methylation R egulation of gene expression is accomplished by transcription factors, histone-modifying enzymes, and chromatin remodeling machinery. The combined action of these three has been implicated in a number of biological processes, including cell cycle control, development, reprogramming, differentiation, and aging. Deregulation of chromatin-modifying enzymes has been strongly linked to the development of cancer. For example, two enzymes that regulate methylation at the histone H3 lysine 4 (H3K4) residue, mixed lineage leukemia-1 (MLL1) and lysine (K)-specific demethylase 5A (KDM5A), have been identified in translocations associated with human leukemia. H3K4 histone methylation states exhibit a highly distinct distribution pattern in the genome. Specifically, H3K4 trimethylation (H3K4me3) is strongly associated with transcriptional activation, with the highest levels observed near transcriptional start sites (TSS). In vitro studies suggest that the four KDM5 enzymes (KDM5A, KDM5B, KDM5C, and KDM5D) are able to remove methylation at lysine 4 of histone H3, and in vivo KDM5A and KDM5B may be recruited to common gene regions (1). This finding leads to multiple questions: (i) Do KDM5 proteins play a role in gene regulation by transcription factors? (ii) Are KDM5 enzymes nonredundant H3K4 demethylases?During differentiation, cells exhibit two novel properties: repression of cell cycle genes associated with permanent cell cycle exit and activation of cell type-specific genes. Histone modifications are thought to be important epigenetic events intimately linked to initiation and maintenance of transcriptional changes for both of these processes. Cell cycle exit is associat...

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“…Ultimately, there may not be a single vulnerability that is characteristic of all RB1 mutant cells, but different strategies may be necessary for specific types of tumors. Changes that activate differentiation programs are one potential strategy (MacLellan et al 2000;Lasorella et al 2005;Lin et al 2011). Recent work has suggested that Notch signaling may be important in mouse models of small-cell lung cancer, one of the most common types of RB1 mutant cancers (George et al 2015).…”

Section: The Translation Of Rb Researchmentioning

confidence: 99%

RB1: a prototype tumor suppressor and an enigma

2016

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The retinoblastoma susceptibility gene (RB1) was the first tumor suppressor gene to be molecularly defined. RB1 mutations occur in almost all familial and sporadic forms of retinoblastoma, and this gene is mutated at variable frequencies in a variety of other human cancers. Because of its early discovery, the recessive nature of RB1 mutations, and its frequency of inactivation, RB1 is often described as a prototype for the class of tumor suppressor genes. Its gene product (pRB) regulates transcription and is a negative regulator of cell proliferation. Although these general features are well established, a precise description of pRB's mechanism of action has remained elusive. Indeed, in many regards, pRB remains an enigma. This review summarizes some recent developments in pRB research and focuses on progress toward answers for the three fundamental questions that sit at the heart of the pRB literature: What does pRB do? How does the inactivation of RB change the cell? How can our knowledge of RB function be exploited to provide better treatment for cancer patients?

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Loss of the retinoblastoma binding protein 2 (RBP2) histone demethylase suppresses tumorigenesis in mice lackingRb1orMen1

Cited by 142 publications

References 69 publications

Characterization of a Linked Jumonji Domain of the KDM5/JARID1 Family of Histone H3 Lysine 4 Demethylases

Characterization of a Linked Jumonji Domain of the KDM5/JARID1 Family of Histone H3 Lysine 4 Demethylases

Coordinated repression of cell cycle genes by KDM5A and E2F4 during differentiation

RB1: a prototype tumor suppressor and an enigma

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