The histone demethylase UTX enables RB-dependent cell fate control

Wang, Jordon K.; Tsai, Miao Chih; Poulin, Gino; Adler, Adam S.; Chen, Shuzhen; Liu, Helen; Shi, Yang; Chang, Howard Y.

doi:10.1101/gad.1882610

Cited by 136 publications

(129 citation statements)

References 36 publications

(52 reference statements)

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“…A parallel study performed by Wang and coworkers showed that the loss of mammalian UTX also results in elevated levels of proliferation (79). Consistent with our work, those authors also implicated the inactivation of Rb function in increased proliferation in response to UTX knockdown.…”

Section: Resultssupporting

confidence: 79%

“…Consistent with our work, those authors also implicated the inactivation of Rb function in increased proliferation in response to UTX knockdown. Similar to our study, Rb itself is not subject to increased H3K27m3 silencing, but the promoters of several genes in the Rb network were found to be occupied and likely controlled by UTX (79). Thus, although the mechanisms of Rb control by UTX proteins (Notch in this study and the Rb network in the study reported previously by Wang et al [79]) are distinct, both studies established the control of the Rb pathway as a common element of cell cycle control by UTX proteins.…”

Section: Resultssupporting

confidence: 71%

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The H3K27me3 Demethylase dUTX Is a Suppressor of Notch- and Rb-Dependent Tumors in Drosophila

Herz

Madden

Chen

et al. 2010

Molecular and Cellular Biology

105

121

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Trimethylated lysine 27 of histone H3 (H3K27me3) is an epigenetic mark for gene silencing and can be demethylated by the JmjC domain of UTX. Excessive H3K27me3 levels can cause tumorigenesis, but little is known about the mechanisms leading to those cancers. Mutants of the Drosophila H3K27me3 demethylase dUTX display some characteristics of Trithorax group mutants and have increased H3K27me3 levels in vivo. Surprisingly, dUTX mutations also affect H3K4me1 levels in a JmjC-independent manner. We show that a disruption of the JmjC domain of dUTX results in a growth advantage for mutant cells over adjacent wild-type tissue due to increased proliferation. The growth advantage of dUTX mutant tissue is caused, at least in part, by increased Notch activity, demonstrating that dUTX is a Notch antagonist. Furthermore, the inactivation of Retinoblastoma (Rbf in Drosophila) contributes to the growth advantage of dUTX mutant tissue. The excessive activation of Notch in dUTX mutant cells leads to tumor-like growth in an Rbf-dependent manner. In summary, these data suggest that dUTX is a suppressor of Notch-and Rbf-dependent tumors in Drosophila melanogaster and may provide a model for UTX-dependent tumorigenesis in humans.

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Section: Resultssupporting

confidence: 79%

Section: Resultssupporting

confidence: 71%

The H3K27me3 Demethylase dUTX Is a Suppressor of Notch- and Rb-Dependent Tumors in Drosophila

Herz

Madden

Chen

et al. 2010

Molecular and Cellular Biology

105

121

View full text Add to dashboard Cite

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“…1). 45 UTX prevents H3K27 methylation and silencing HBP1, thereby enforcing cell cycle arrest by pRB. Consistently, UTX depletion results in elevated levels of proliferation.…”

Section: Utx/kdm6amentioning

confidence: 99%

Epigenetic regulation of cancer growth by histone demethylases

Lim

Metzger

Schüle

et al. 2010

Intl Journal of Cancer

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Cancer is traditionally viewed as a primarily genetic disorder. However, it is now increasingly apparent that epigenetic abnormalities play a fundamental role in cancer development. Aberrant expression of histone-modifying enzymes has been implicated in the course of tumor initiation and progression. The discovery of a large number of histone demethylases suggests an important role for dynamic regulation of histone methylation in biological processes. The observation that overexpression, amplification or mutations of several histone demethylases have been found in many types of tumors, raise the possibility of using these enzymes as diagnostic tools as well as pave a way for the discovery of novel therapeutic targets and treatment modalities. Here, we review the current knowledge of the potential role of H3K4, H3K9 and H3K27 histone demethylases in tumorigenesis.Recently, it has become apparent that not only genetic mutations but also epigenetic alterations lead to the activation of oncogenes and the loss of function of tumor-suppressor genes. Since epigenetic abnormalities in DNA methylation patterns as well as histone modifications are potentially reversible in contrast to gene mutations, much effort has been directed toward understanding the mechanism of epigenetic aberration to develop epigenetic therapies. Indeed, inhibitors of histone deacetylases (HDACs) and DNA methyltransferases (DNMTs) have been approved for treatment of certain types of cancers. Recently, overexpression, amplification or mutations of several histone demethylases have been linked to many types of tumor, raising the possibility of using these enzymes as diagnostic tools and therapeutic targets. Here, we focus mainly on the potential role of some selected histone lysine demethylases in tumorigenesis.The N-terminal tails of histones are subjected to several types of post-translational modifications, including acetylation, methylation, phosphorylation and ubiquitination. The combination of these modifications determines chromatin structure and transcriptional activation or repression of genes. In contrast to other histone modifications, the importance of histone methylations is highlighted because of their enormously specific dynamics with respect to gene regulation. Histone lysine residues on histone H3 and H4 (H3K4, H3K9, H3K27, H3K36, H3K79 and H4K20) can become mono-, dior trimethylated. These modifications are regulated by two classes of enzymes with opposing activities: histone methyltransferases and histone lysine demethylases. LSD1, also known as AOF2 and KDM1, is the first discovered histone lysine demethylase that belongs to the flavin adenine dinucleotide-dependent enzyme family. 1 Subsequently, another family of histone lysine demethylases structurally different from LSD1 was described, all of which sharing the conserved jumonji C (JmjC) domain (Table 1). H3K4 Demethylases in Cancer LSD1/KDM1ATri-and dimethylated H3K4 (H3K4me3/2) are often found at actively transcribed genes. Although H3K4me3 is highly enriched around transcrip...

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“…KDM6A catalyzes the demethylation of tri/dimethylated histone H3 (48). This gene regulates cell proliferation and acts as a tumor suppressor via pRb-dependent pathways (49). SETD2 is a methyltransferase specific to histone H3 lysine-36, and methylation of this residue is associated with active chromatin.…”

mentioning

confidence: 99%

The role of components of the chromatin modification machinery in carcinogenesis of clear cell carcinoma of the ovary (Review)

et al. 2011

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Abstract. Recent data have provided information regarding the profiles of clear cell carcinoma of the ovary (CCC) with adenine-thymine rich interactive domain 1A (ARID1A) mutations. The purpose of this review was to summarize current knowledge regarding the molecular mechanisms involved in CCC tumorigenesis and to describe the central role played by the aberrant chromatin remodeling. The present article reviews the English-language literature for biochemical studies on the ARID1A mutation and chromatin remodeling in CCC. ARID1A is responsible for directing the SWI/SNF complex to target promoters and regulates the transcription of certain genes by altering the chromatin structure around those genes. The mutation spectrum of ARID1A was enriched for C to T transitions. CCC and clear cell renal cell carcinoma (ccRCC) resemble each other pathogenetically. Dysfunction of the ARID1A protein, which occurs with VHL mutations in ccRCC, is responsible for loss of the assembly of the ARID1A-mediated histone H2B complex. Therefore, ARID1A acts as a chromatin remodeling modifier, which stimulates cell signaling that can lead to cell cycle arrest and cell death in the event of DNA damage. The dysfunction of ARID1A may result in susceptibility to CCC carcinogenesis through a defect in the repair or replication of damaged DNA. IntroductionEpithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy worldwide. Epidemiology calculations of lifetime risk for EOC are that 1 in 55 women is likely to develop EOC during their lifetime (1). Since EOC is more likely to be advanced stage with unfavorable tumor biology, there are serious limitations to the surgical and oncological treatment available. Therefore, it is crucial to determine the earliest possible diagnosis. Early diagnosis and surgical resection offer patients the best opportunity of excellent long-term survival. On the other hand, patients who either present with metastatic disease or develop distant relapse within 6 months after surgery and chemotherapy have a poor prognosis. Among EOC, clear cell carcinomas of the ovary (CCC) are frequently characterized by chemoresistance and recurrence, resulting in a poor prognosis (2). Since CCC are resistant to conventional cytotoxic (platinum plus taxan-based) chemotherapy, the prognosis is mostly poor (3). In the USA, the incidence of CCC is 5% of all EOC, but the incidence in Japan is reported to be over 20% of all EOC. Thus, Japanese oncologists have focused on investigating the molecular pathogenesis and treatment strategies of CCC.At present, little is known about the molecular genetic mechanisms that are involved in CCC tumorigenesis. Accumulated somatic mutations found in a subset of cancer genes are frequently noted. Such mutations include insertions/deletions (indels) and base substitutions that act as the 'driver mutations' in oncogenesis. These mutations result in the activation of proto-oncogenes (gain of function) or the inhibition of tumor suppressor genes (loss of function) during the process of carcinoge...

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The histone demethylase UTX enables RB-dependent cell fate control

Cited by 136 publications

References 36 publications

The H3K27me3 Demethylase dUTX Is a Suppressor of Notch- and Rb-Dependent Tumors in Drosophila

The H3K27me3 Demethylase dUTX Is a Suppressor of Notch- and Rb-Dependent Tumors in Drosophila

Epigenetic regulation of cancer growth by histone demethylases

The role of components of the chromatin modification machinery in carcinogenesis of clear cell carcinoma of the ovary (Review)

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