Mice deficient in the candidate tumor suppressor gene Hic1 exhibit developmental defects of structures affected in the Miller-Dieker syndrome

Carter, M. G.

doi:10.1093/hmg/9.3.413

Cited by 117 publications

(82 citation statements)

References 32 publications

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“…P57KIP2 is the only CIP/KIP gene whose targeted disruption results in developmental abnormalities, leading to death soon after birth (67). Thus, in addition to its role in cell cycle regulation, P57KIP2 is essential for normal development, exactly as HIC1 since homozygous Hic1 Ϫ/Ϫ mouse embryos display severe developmental defects culminating in perinatal death (6). The repression of P57KIP2 that we observed between quiescent and growing fibroblasts could thus be only partially related to cell cycle regulation but also to a yet-unidentified developmental process.…”

Section: Discussionmentioning

confidence: 99%

Differential Regulation of HIC1 Target Genes by CtBP and NuRD, via an Acetylation/SUMOylation Switch, in Quiescent versus Proliferating Cells

Rechem

Boulay

Pinte

et al. 2010

Molecular and Cellular Biology

110

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The tumor suppressor gene HIC1 encodes a transcriptional repressor involved in regulatory loops modulating P53-dependent and E2F1-dependent cell survival, growth control, and stress responses. Despite its importance, few HIC1 corepressors and target genes have been characterized thus far. Using a yeast two-hybrid approach, we identify MTA1, a subunit of the NuRD complex, as a new HIC1 corepressor. This interaction is regulated by two competitive posttranslational modifications of HIC1 at lysine 314, promotion by SUMOylation, and inhibition by acetylation. Consistent with the role of HIC1 in growth control, we demonstrate that HIC1/MTA1 complexes bind on two new target genes, Cyclin D1 and p57KIP2 in quiescent but not in growing WI38 cells. In addition, HIC1/MTA1 and HIC1/CtBP complexes differentially bind on two mutually exclusive HIC1 binding sites (HiRE) on the SIRT1 promoter. SIRT1 transcriptional activation induced by short-term serum starvation coincides with loss of occupancy of the distal sites by HIC1/MTA1 and HIC1/CtBP. Upon longer starvation, both complexes are found but on a newly identified proximal HiRE that is evolutionarily conserved and specifically enriched with repressive histone marks. Our results decipher a mechanistic link between two competitive posttranslational modifications of HIC1 and corepressor recruitment to specific genes, leading to growth control.HIC1 (Hypermethylated in Cancer 1), a tumor suppressor gene frequently deleted or epigenetically silenced in human cancers, encodes a transcriptional repressor (7,20,65). A regulatory feedback loop between HIC1 and P53 has been deciphered. HIC1 is a direct target gene of P53 (5, 24, 65). HIC1 directly represses the transcription of SIRT1, a NAD ϩ -dependent class III histone deacetylase (HDAC) that deacetylates and inactivates P53, thereby modulating P53-dependent DNA damage responses (8). We have shown that SIRT1 also deacetylates HIC1. In contrast to P53, this deacetylation activates HIC1 by strengthening its transcriptional repression potential (59).Aside from P53, SIRT1 and HIC1 have also been implicated in a feedback regulatory loop with E2F1. E2F1 is a crucial activator of SIRT1 transcription in response to DNA damage, but SIRT1 binds and deacetylates E2F1 that inhibits E2F1-mediated gene activation (30, 66). In addition, E2F1 directly activates HIC1 (27) and HIC1 directly represses the E2F1 promoter in quiescent but not in G 1 human fibroblasts, which contributes to the growth suppression induced by serum deprivation (71). Thus, HIC1 is placed at the intersection of complex regulatory loops modulating p53-dependent and E2F1-dependent cell survival, growth control, and stress responses (15).HIC1 encodes a sequence-specific transcriptional repressor with five Krüppel-like C 2 H 2 zinc fingers mediating DNA binding to a HIC1 responsive element (HiRE), (C/G)NG(C/ G)GGGCA(C/A)CC (48). To date, SIRT1, ATOH1 (a proneuronal transcription factor) (4), E2F1, CXCR7 (a receptor for the chemokine CXCL12) (62), and ephrin-A1 (a cell surface liga...

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Section: Discussionmentioning

confidence: 99%

Differential Regulation of HIC1 Target Genes by CtBP and NuRD, via an Acetylation/SUMOylation Switch, in Quiescent versus Proliferating Cells

Rechem

Boulay

Pinte

et al. 2010

Molecular and Cellular Biology

110

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“…Other transcription factors found in the cluster were recognized as being functionally involved in several complex developmental processes. This is the case for NFI/A, which is expressed in a wide variety of embryonic and adult tissues (Chaudhry et al, 1997); NFI/B, which is implicated in normal lung development (Grunder et al, 2002); Hic-1, a candidate tumor suppressor gene, whose ablation produces the developmental defects observed in the Miller-Dieker syndrome (acrania, exencephaly, cleft palate, limb abnormalities and omphalocele) (Carter et al, 2000); Peg3/Pw1, a zinc finger containing protein, shown to be a necessary participant of p53-mediated apoptosis in fibroblasts (Relaix et al, 2000) and neurons (Deng and Wu, Journal of Cell Science 117 (19) …”

Section: Gene Profile Of Mesoangioblastsmentioning

confidence: 99%

TGFβ/BMP activate the smooth muscle/bone differentiation programs in mesoangioblasts

Tagliafico

Brunelli²,

Bergamaschi

et al. 2004

Journal of Cell Science

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Mesoangioblasts are vessel-derived stem cells that can be induced to differentiate into different cell types of the mesoderm such as muscle and bone. The gene expression profile of four clonal derived lines of mesoangioblasts was determined by DNA micro-array analysis: it was similar in the four lines but different from 10T1/2 embryonic fibroblasts, used as comparison. Many known genes expressed by mesoangioblasts belong to response pathways to developmental signalling molecules, such as Wnt or TGFβ/BMP. Interestingly, mesoangioblasts express receptors of the TGFβ/BMP family and several Smads and, accordingly, differentiate very efficiently into smooth muscle cells in response to TGFβ and into osteoblasts in response to BMP. In addition, insulin signalling promotes adipogenic differentiation, possibly through the activation of IGF-R. Several Wnts and Frizzled, Dishevelled and Tcfs are expressed, suggesting the existence of an autocrine loop for proliferation and indeed, forced expression of Frzb-1 inhibits cell division. Mesoangioblasts also express many neuro-ectodermal genes and yet undergo only abortive neurogenesis, even after forced expression of neurogenin 1 or 2, MASH or NeuroD. Finally, mesoangioblasts express several pro-inflammatory genes, cytokines and cytokine receptors, which may explain their ability to be recruited by tissue inflammation. Our data define a unique phenotype for mesoangioblasts, explain several of their biological features and set the basis for future functional studies on the role of these cells in tissue histogenesis and repair.

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“…Although homozygous disruption of HIC1 impairs development and leads to embryonic and perinatal lethality (11), mice with heterozygous HIC1 inactivation (Hic1 þ/À ) have the propensity to form spontaneous tumors (12). The presence of HIC1 silence is associated with preneoplastic conditions such as smoker's lung, colonic polyps, and cirrhotic liver (13).…”

Section: Introductionmentioning

confidence: 99%

HIC1 Modulates Prostate Cancer Progression by Epigenetic Modification

Zheng

Wang

Sun

et al. 2013

Clinical Cancer Research

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Purpose: Prostate cancer is the second leading cause of cancer deaths among men in Western counties, which has also occurred in Chinese male with markedly increasing incidence in recent years. Although the mechanism underlying its progression still remains unclear, epigenetic modifications are important ethological parameters. The purpose of this study is to determine the methylation status and function of hypermethylatioted in cancer 1 (HIC1) in prostate cancer progression.Experimental Design: The methylation status of HIC1 promoter was assayed in cell lines, tissues, and plasma of patients with prostate cancer by using methylation-specific PCR and bisulfate sequencing PCR. The ability of HIC1 to regulate proliferation, migration, and invasion was assessed by MTT, scratch-healing assay, and reconstituted extracellular matrices in porous culture chambers. Tumorigenesis, metastases, and bone destruction were analyzed in mice bearing prostate cancer cells restoring HIC1 by using Xenogen IVIS with radiographic system and small-animal positron emission tomography computed tomographic images. Microarrays were searched for genes that had correlated expression with HIC1 mRNA. Reporter gene assays were used to determine whether HIC1 affected the expression of CXCR7, and chromatin immunoprecipitation was used to determine whether HIC1 bound to CXCR7 promoters. All P values were determined using 2-sided tests.Results: The methylation status of 11 CpG sites within HIC1 promoter was abundantly methylated in cell lines, tissues, and plasma of patients with prostate cancer compared with those of respective normal controls. Restoring HIC1 expression in prostate cancer cells markedly inhibited proliferation, migration, and invasion and induced the apoptosis in these cells. Moreover, mice bearing prostate cancer-restoring HIC1 cells had a marked effect on reducing tumor growth, multiple tissue metastases, and bone destruction. Notably, we also identified that the chemokine receptor CXCR7 is a direct downstream target gene of HIC1. Finally, we showed that CXCR7 promoter in prostate cancer cells is negatively regulated by HIC1, which may be responsible for prostate cancer progression.Conclusions: Our data show for the first time that hypermethylation of HIC1 promoter results in loss of its repressive function, responsible for prostate cancer progression and invasion. These findings suggest that therapies targeting epigenetic events regulating HIC1 expression may provide a more effective strategy for prostate cancer treatment.

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Mice deficient in the candidate tumor suppressor gene Hic1 exhibit developmental defects of structures affected in the Miller-Dieker syndrome

Cited by 117 publications

References 32 publications

Differential Regulation of HIC1 Target Genes by CtBP and NuRD, via an Acetylation/SUMOylation Switch, in Quiescent versus Proliferating Cells

Differential Regulation of HIC1 Target Genes by CtBP and NuRD, via an Acetylation/SUMOylation Switch, in Quiescent versus Proliferating Cells

TGFβ/BMP activate the smooth muscle/bone differentiation programs in mesoangioblasts

HIC1 Modulates Prostate Cancer Progression by Epigenetic Modification

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