Negative Regulation of Hypoxic Responses via Induced Reptin Methylation

Lee, Jason S.; Kim, Yun‐Ho; Kim, Ik Soo; Kim, Bogyou; Choi, Hee June; Lee, Ji Min; Shin, H; Kim, Jung Hwa; Kim, Ji Young; Seo, Sang-Beom; Lee, Ho; Binda, Olivier; Gozani, Or; Semenza, Gregg L.; Kim, Minhyung; Kim, Keun Il; Hwang, Daehee; Baek, Sung Hee

doi:10.1016/j.molcel.2010.06.008

Cited by 151 publications

(159 citation statements)

References 38 publications

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“…In addition, they can transfer the methyl moiety to non-histone substrates. For example, G9a has been found to methylate p53, WIZ, CDYL1, ACINUS, and Reptin [19,20,26,27]. Similarly, Chakraborty et al [28] have reported that SUV39H1 interacts with the N-terminus of Runx1 (alternatively called AML1), and suggested that SUV39H1 inhibits the transcriptional activity of Runx1 by blocking its DNA-binding ability.…”

Section: Discussionmentioning

confidence: 97%

Plant homeodomain finger protein 2 promotes bone formation by demethylating and activating Runx2 for osteoblast differentiation

et al. 2014

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Plant homeodomain finger protein 2 (PHF2), which contains a plant homeodomain and a Jumonji-C domain, is an epigenetic regulator that demethylates lysine 9 in histone 3 (H3K9me2). On the other hand, runt-related transcription factor 2 (Runx2) plays essential roles in bone development and regeneration. Given previous reports that the PHF2 mutation can cause dwarfism in mice and that PHF2 expression is correlated with that of Runx2 in differentiating thymocytes, we investigated whether PHF2 regulates Runx2-mediated bone formation. Overexpression of PHF2 facilitated bone development in newborn mice, and viral shRNA-mediated knockdown of PHF2 delayed calvarial bone regeneration in adult rats. In primary osteoblasts and C2C12 precursor cells, PHF2 enhances osteoblast differentiation by demethylating Runx2, while suppressor of variegation 3-9 homolog 1 (SUV39H1) inhibits bone formation by methylating it. The PHF2-Runx2 interaction is mediated by the Jumonji-C and Runt domains of the two proteins, respectively. The interaction between Runx2 and osteocalcin promoter is regulated by the methylation status of Runx2, i.e., the interaction is augmented when Runx2 is demethylated. Our results suggest that SUV39H1 and PHF2 reciprocally regulate osteoblast differentiation by modulating Runx2-driven transcription at the post-translational level. This study may provide a theoretical basis for the development of new therapeutic modalities for patients with impaired bone development or delayed fracture healing.

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Section: Discussionmentioning

confidence: 97%

Plant homeodomain finger protein 2 promotes bone formation by demethylating and activating Runx2 for osteoblast differentiation

et al. 2014

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“…In breast cancer, overexpression of HIF-1α or HIF-2α is associated with metastasis, treatment failure, and patient mortality (21)(22)(23)(24)(25)(26). HIFs are required for lymph node and lung metastasis in both autochthonous (27) and orthotopic (28)(29)(30) mouse models of breast cancer and activate the transcription of genes encoding proteins that are required for multiple steps in the invasion and metastasis of breast cancer cells (28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38).…”

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confidence: 99%

Hypoxia-inducible factors and RAB22A mediate formation of microvesicles that stimulate breast cancer invasion and metastasis

Wang

Gilkes²,

Takano³

et al. 2014

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

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Extracellular vesicles such as exosomes and microvesicles (MVs) are shed by cancer cells, are detected in the plasma of cancer patients, and promote cancer progression, but the molecular mechanisms regulating their production are not well understood. Intratumoral hypoxia is common in advanced breast cancers and is associated with an increased risk of metastasis and patient mortality that is mediated in part by the activation of hypoxiainducible factors (HIFs). In this paper, we report that exposure of human breast cancer cells to hypoxia augments MV shedding that is mediated by the HIF-dependent expression of the small GTPase RAB22A, which colocalizes with budding MVs at the cell surface. Incubation of naïve breast cancer cells with MVs shed by hypoxic breast cancer cells promotes focal adhesion formation, invasion, and metastasis. In breast cancer patients, RAB22A mRNA overexpression in the primary tumor is associated with decreased overall and metastasis-free survival and, in an orthotopic mouse model, RAB22A knockdown impairs breast cancer metastasis.orthotopic transplantation | triple negative breast cancer | oxygen | tumor microenvironment | mammary fat pad implantation

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“…The histone demethylase jumonji domain (JMJD) containing protein 1A demethylates dimethylated lysine 9 of histone H3 (H3K9me2) and enhances transcription of the HIF-1 target genes SLC2A3 and KDM3A (25). The ATP-dependent chromatin remodeling factors Pontin and Reptin regulate HIF-1 transcriptional activity as well (26,27). Pontin interacts with HIF-1α to enhance transcription of the HIF-1 target gene ETS1, thereby promoting migration of MCF-7 breast cancer cells (26).…”

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confidence: 99%

Histone demethylase JMJD2C is a coactivator for hypoxia-inducible factor 1 that is required for breast cancer progression

Luo¹,

Chang²,

Zhong³

et al. 2012

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

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Hypoxia-inducible factor 1 (HIF-1) activates transcription of genes encoding proteins that play key roles in breast cancer biology. We hypothesized that interaction of HIF-1 with epigenetic regulators may increase HIF-1 transcriptional activity, and thereby promote breast cancer progression. We report that the histone demethylase jumonji domain containing protein 2C (JMJD2C) selectively interacts with HIF-1α, but not HIF-2α, and that HIF-1α mediates recruitment of JMJD2C to the hypoxia response elements of HIF-1 target genes. JMJD2C decreases trimethylation of histone H3 at lysine 9, and enhances HIF-1 binding to hypoxia response elements, thereby activating transcription of BNIP3, LDHA, PDK1, and SLC2A1, which encode proteins that are required for metabolic reprogramming, as well as LOXL2 and L1CAM, which encode proteins that are required for lung metastasis. JMJD2C expression is significantly associated with expression of GLUT1, LDHA, PDK1, LOX, LOXL2, and L1CAM mRNA in human breast cancer biopsies. JMJD2C knockdown inhibits breast tumor growth and spontaneous metastasis to the lungs of mice following mammary fat pad injection. Taken together, these findings establish an important epigenetic mechanism that stimulates HIF-1-mediated transactivation of genes encoding proteins involved in metabolic reprogramming and lung metastasis in breast cancer.H3K9me3 | SILAC | chromatin immunoprecipitation | gene expression

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Negative Regulation of Hypoxic Responses via Induced Reptin Methylation

Cited by 151 publications

References 38 publications

Plant homeodomain finger protein 2 promotes bone formation by demethylating and activating Runx2 for osteoblast differentiation

Plant homeodomain finger protein 2 promotes bone formation by demethylating and activating Runx2 for osteoblast differentiation

Hypoxia-inducible factors and RAB22A mediate formation of microvesicles that stimulate breast cancer invasion and metastasis

Histone demethylase JMJD2C is a coactivator for hypoxia-inducible factor 1 that is required for breast cancer progression

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