Genetic and Functional Studies Implicate <i>HIF1</i>α as a 14q Kidney Cancer Suppressor Gene

Shen, Chuan; Beroukhim, Rameen; Schumacher, Steven E.; Zhou, Jing; Chang, Michelle; Signoretti, Sabina; Kaelin, William G.

doi:10.1158/2159-8290.cd-11-0098

Cited by 363 publications

(392 citation statements)

References 51 publications

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“…In a more positive direction, our data strengthen the rationale for drug discovery efforts aimed at sustaining ERβ expression and diminishing HIF-1 activation, given that HIF-1 has been implicated in the pathogenesis of highly aggressive cancers (9,23,44). This strategy should be tumor specific, however, because HIF-1α can function as a tumor suppressor gene in some cancers (45).…”

Section: Discussionsupporting

confidence: 65%

Estrogen receptor β sustains epithelial differentiation by regulating prolyl hydroxylase 2 transcription

Mak

Chang

Pursell

et al. 2013

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

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Estrogen receptor β (ERβ) promotes the degradation of hypoxia inducible factor 1α (HIF-1α), which contributes to the ability of this hormone receptor to sustain the differentiation of epithelial and carcinoma cells. Although the loss of ERβ and consequent HIF-1 activation occur in prostate cancer with profound consequences, the mechanism by which ERβ promotes the degradation of HIF-1α is unknown. We report that ERβ regulates the ligand (3β-adiol)-dependent transcription of prolyl hydroxylase 2 (PHD2) also known as Egl nine homolog 1 (EGLN1), a 2-oxoglutarate-dependent dioxygenase that hydroxylates HIF-1α and targets it for recognition by the von Hippel-Lindau tumor suppressor and consequent degradation. ERβ promotes PHD2 transcription by interacting with a unique estrogen response element in the 5′ UTR of the PHD2 gene that functions as an enhancer. PHD2 itself is critical for maintaining epithelial differentiation. Loss of PHD2 expression or inhibition of its function results in dedifferentiation with characteristics of an epithelial-mesenchymal transition, and exogenous PHD2 expression in dedifferentiated cells can restore an epithelial phenotype. Moreover, expression of HIF-1α in cells that express PHD2 does not induce dedifferentiation but expression of HIF-1α containing mutations in the proline residues that are hydroxylated by PHD2 induces dedifferentiation. These data describe a unique mechanism for the regulation of HIF-1α stability that involves ERβ-mediated transcriptional regulation of PHD2 and they highlight an unexpected role for PHD2 in maintaining epithelial differentiation.T he role of estrogen receptors (ERs), which are transcription factors belonging to the steroid/thyroid nuclear receptor superfamily (1-3), in regulating epithelial differentiation is an emerging area of considerable biological interest and pathological relevance. In the prostate, the discovery of ERβ (4, 5) has generated intense interest in the roles played by this ER in several tissues including prostate and breast epithelia (6-11). Increasing evidence supports the hypothesis that ERβ functions to maintain epithelial differentiation in the prostate and breast (9,10,12,13). In the normal prostate, ERβ contributes to epithelial differentiation as evidenced by the observation that ERβ knockout mice exhibit altered differentiation in the ventral prostate, whereas the glands of ERα knockout mice lack these lesions and appear to be normal (12). ERβ in human prostate cancer is of substantial relevance because there is an inverse relationship between the expression of ERβ and highly invasive prostate cancer (9,14). In pursuit of a functional basis for this relationship, we demonstrated that ERβ sustains an epithelial phenotype and impedes a mesenchymal transition in prostate cancer and we identified a metabolite of dihydrotestosterone, 5α-androstane-3β,17β4-diol (3β-adiol) as the specific ERβ ligand that mediates this function (9). This observation is in agreement with the recent findings that 3β-adiol is a natural ligand for ERβ in ...

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Section: Discussionsupporting

confidence: 65%

Estrogen receptor β sustains epithelial differentiation by regulating prolyl hydroxylase 2 transcription

Mak

Chang

Pursell

et al. 2013

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

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“…The data shown here indicate that defects in DNMT3a-mediated epigenetic silencing of EPAS1 may explain the unscheduled expression of HIF-2α mRNA in early cancer. Interestingly, the appearance of HIF-2α mRNA in renal cancers is often associated with a decrease or outright absence of HIF-1α mRNA, stemming from alterations in the HIF-1α locus (41). One possible model to explain this apparent switch between HIF-1α and HIF-2α would be a concomitant inactivation of HIF-1α and a loss of DNMT3a activity, which would relieve EPAS1 from its epigenetic restraint.…”

Section: Discussionmentioning

confidence: 99%

DNMT3a epigenetic program regulates the HIF-2α oxygen-sensing pathway and the cellular response to hypoxia

Lachance

Uniacke

Audas

et al. 2014

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

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Epigenetic regulation of gene expression by DNA methylation plays a central role in the maintenance of cellular homeostasis. Here we present evidence implicating the DNA methylation program in the regulation of hypoxia-inducible factor (HIF) oxygensensing machinery and hypoxic cell metabolism. We show that DNA methyltransferase 3a (DNMT3a) methylates and silences the HIF-2α gene (EPAS1) in differentiated cells. Epigenetic silencing of EPAS1 prevents activation of the HIF-2α gene program associated with hypoxic cell growth, thereby limiting the proliferative capacity of adult cells under low oxygen tension. Naturally occurring defects in DNMT3a, observed in primary tumors and malignant cells, cause the unscheduled activation of EPAS1 in early dysplastic foci. This enables incipient cancer cells to exploit the HIF-2α pathway in the hypoxic tumor microenvironment necessary for the formation of cellular masses larger than the oxygen diffusion limit. Reintroduction of DNMT3a in DNMT3a-defective cells restores EPAS1 epigenetic silencing, prevents hypoxic cell growth, and suppresses tumorigenesis. These data support a tumor-suppressive role for DNMT3a as an epigenetic regulator of the HIF-2α oxygensensing pathway and the cellular response to hypoxia.

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Section: Discussionmentioning

confidence: 99%

“…HIF-1a resides on chromosome 14q, whose homozygous deletion leads to absent protein production [28]. In some cases, alternative mRNA splicing around deleted HIF-1a exonic sequence leads to the production of aberrant HIF-1a isoforms [28]. Although rare, intragenic HIF-1a mutations, including missense mutations, have been described in clear renal carcinoma tumors [28].…”

Section: Discussionmentioning

confidence: 99%

“…In some cases, alternative mRNA splicing around deleted HIF-1a exonic sequence leads to the production of aberrant HIF-1a isoforms [28]. Although rare, intragenic HIF-1a mutations, including missense mutations, have been described in clear renal carcinoma tumors [28]. Besides mutational events, inherited polymorphisms might also play a role in RCC carcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

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VHL and HIF-1α: gene variations and prognosis in early-stage clear cell renal cell carcinoma

et al. 2014

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Von Hipple-Lindau gene (VHL) inactivation represents the most frequent abnormality in clear cell renal cell carcinoma (ccRCC). Hypoxia-inducible factor-1a (HIF-1a) expression is regulated by O 2 level. In normal O 2 conditions, VHL binds HIF-1a and allows HIF-1a proteasomal degradation. A single-nucleotide polymorphism (SNP) has been found located in the oxygen-dependent degradation domain at codon 582 (C1772T, rs11549465, Pro582Ser). In hypoxia, VHL/HIF-1a interaction is abolished and HIF-1a activates target genes in the nucleus. This study analyzes the impact of genetic alterations and protein expression of VHL and the C1772T SNP of HIF-1a gene (HIF-1a) on prognosis in early-stage ccRCC (pT1a, pT1b, and pT2). Mutational analysis of the entire VHL sequence and the genotyping of HIF-1a C1772T SNP were performed together with VHL promoter methylation analysis and loss of heterozygosis (LOH) analysis at (3p25) locus. Data obtained were correlated with VHL and HIF-1a protein expression and with tumor-specific survival (TSS). VHL mutations, methylation status, and LOH were detected in 51, 11, and 12 % of cases, respectively. Our results support the association between biallelic alterations and/or VHL silencing with a worse TSS. Moreover, we found a significant association between the HIF-1a C1772C genotype and a worse TSS. The same association was found when testing the presence of HIF-1a protein in the nucleus. Our results highlight the role of VHL/HIF-1a pathway in RCC and support the molecular heterogeneity of earlystage ccRCC. More important, we show the involvement of HIF-1a C1772T SNP in ccRCC progression.

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Genetic and Functional Studies Implicate HIF1α as a 14q Kidney Cancer Suppressor Gene

Cited by 363 publications

References 51 publications

Estrogen receptor β sustains epithelial differentiation by regulating prolyl hydroxylase 2 transcription

Estrogen receptor β sustains epithelial differentiation by regulating prolyl hydroxylase 2 transcription

DNMT3a epigenetic program regulates the HIF-2α oxygen-sensing pathway and the cellular response to hypoxia

VHL and HIF-1α: gene variations and prognosis in early-stage clear cell renal cell carcinoma

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