Regulation of the Histone Demethylase JMJD1A by Hypoxia-Inducible Factor 1α Enhances Hypoxic Gene Expression and Tumor Growth

Krieg, Adam J.; Rankin, Erinn B.; Chan, Denise A.; Razorenova, Olga V.; Fernandez, Sully; Giaccia, Amato J.

doi:10.1128/mcb.00444-09

Cited by 314 publications

(334 citation statements)

References 59 publications

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“…However, we did find a correlation of CDCP1 cell surface expression with patient outcome: 50% of patients positive for CDCP1 on the membrane die by 90 mo of the followup; >75% of patients with negative or cytoplasmic CDCP1 are alive at the end of the followup, which is 119 mo. Thus, our data suggest that CDCP1 expression might play a crucial role in (12). We found that CDCP1 mRNA was increased with VHL loss (RCC4 vs. RCC-VHL cells), and CDCP1 expression was induced at least threefold upon hypoxic exposure of RCC4-VHL (Fig.…”

mentioning

confidence: 50%

VHL loss in renal cell carcinoma leads to up-regulation of CUB domain-containing protein 1 to stimulate PKCδ-driven migration

Razorenova

Finger

Colavitti

et al. 2011

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

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A common genetic mutation found in clear cell renal cell carcinoma (CC-RCC) is the loss of the von Hippel-Lindau (VHL) gene, which results in stabilization of hypoxia-inducible factors (HIFs), and contributes to cancer progression and metastasis. CUB-domain-containing protein 1 (CDCP1) was shown to promote metastasis in scirrhous and lung adenocarcinomas as well as in prostate cancer. In this study, we established a molecular mechanism linking VHL loss to induction of the CDCP1 gene through the HIF-1/2 pathway in renal cancer. Also, we report that Fyn, which forms a complex with CDCP1 and mediates its signaling to PKCδ, is a HIF-1 target gene. Mechanistically, we found that CDCP1 specifically regulates phosphorylation of PKCδ, but not of focal adhesion kinase or Crk-associated substrate. Signal transduction from CDCP1 to PKCδ leads to its activation, increasing migration of CC-RCC. Furthermore, patient survival can be stratified by CDCP1 expression at the cell surface of the tumor. Taken together, our data indicates that CDCP1 protein might serve as a therapeutic target for CC-RCC.

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mentioning

confidence: 50%

VHL loss in renal cell carcinoma leads to up-regulation of CUB domain-containing protein 1 to stimulate PKCδ-driven migration

Razorenova

Finger

Colavitti

et al. 2011

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

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“…In parallel, ChIP-chip analysis was used to identify genes bound by HIF-1 or HIF-2 within promoter regions of RCC4 cells. The screen identified several known HIF target genes, including vascular endothelial growth factor (VEGF), providing validity for our ChIP-chip analysis (15). We were particularly interested in identifying HIF targets that could be molecular targets for ccRCC therapy, including secreted factors, receptors, or kinases.…”

Section: Resultsmentioning

confidence: 99%

“…To identify novel molecular targets involved in ccRCC tumor progression and metastasis, we performed a directed screen by combining high-throughput chromatin immunoprecipitation (ChIP-chip) with gene expression analysis to identify functionally relevant HIF target genes (15) (Fig. 1A).…”

Section: Resultsmentioning

confidence: 99%

Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET

Rankin

Fuh

Castellini

et al. 2014

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

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Dysregulation of the von Hippel-Lindau/hypoxia-inducible transcription factor (HIF) signaling pathway promotes clear cell renal cell carcinoma (ccRCC) progression and metastasis. The protein kinase GAS6/AXL signaling pathway has recently been implicated as an essential mediator of metastasis and receptor tyrosine kinase crosstalk in cancer. Here we establish a molecular link between HIF stabilization and induction of AXL receptor expression in metastatic ccRCC. We found that HIF-1 and HIF-2 directly activate the expression of AXL by binding to the hypoxia-response element in the AXL proximal promoter. Importantly, genetic and therapeutic inactivation of AXL signaling in metastatic ccRCC cells reversed the invasive and metastatic phenotype in vivo. Furthermore, we define a pathway by which GAS6/AXL signaling uses lateral activation of the met proto-oncogene (MET) through SRC proto-oncogene nonreceptor tyrosine kinase to maximize cellular invasion. Clinically, AXL expression in primary tumors of ccRCC patients correlates with aggressive tumor behavior and patient lethality. These findings provide an alternative model for SRC and MET activation by growth arrest-specific 6 in ccRCC and identify AXL as a therapeutic target driving the aggressive phenotype in renal clear cell carcinoma.targeted therapy | kidney cancer | VHL | hepatocellular carcinoma K idney cancer is a leading cause of cancer-related deaths in the United States. Metastasis to distant organs including the lung, bone, liver, and brain is the primary cause of death in kidney cancer patients, as only 12% of patients with metastatic kidney cancer will survive past 5 y, in comparison with 92% of patients with a localized disease (1). Because kidney cancer is chemo-and radiation-resistant, targeted therapies are needed for the prevention and management of metastatic kidney cancer.The von Hippel-Lindau (VHL)-hypoxia-inducible transcription factor (HIF) pathway is a critical regulator of clear cell renal cell carcinoma (ccRCC) tumor initiation and metastasis. VHL is a classic tumor suppressor controlling tumor initiation in ∼90% of ccRCC tumors (2, 3). VHL is the substrate recognition component of an E3 ubiquitin ligase complex containing the elongins B and C (4, 5), Cullin-2 (6), and Rbx1 (7) that targets the hydroxylated, oxygen-sensitive α-subunits of HIFs (HIF-1, -2, and -3) for ubiquitination and degradation by the 26S proteasome (8, 9). Thus, the primary function ascribed to VHL is the regulation of HIF protein stability. In VHL-deficient tumors, HIF transcriptional activity is constitutively active and contributes to both ccRCC tumor initiation and metastasis (8-11). Although many downstream HIF targets controlling ccRCC tumor initiation have been defined, key targets involved in ccRCC metastasis remain to be identified.AXL, a member of the TAM family of receptor tyrosine kinases (RTKs), has recently been described as an essential mediator of cancer metastasis. Additionally, AXL has been reported to mediate RTK crosstalk and resistance to targeted kina...

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“…13,34 Recent studies have shown that JMJD1A is the target of hypoxia-inducible transcription factors and under hypoxia JMJD1A increases a subset of hypoxia-inducible genes enhancing tumor growth. 35 …”

Section: Jmjd1/kdm3mentioning

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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Regulation of the Histone Demethylase JMJD1A by Hypoxia-Inducible Factor 1α Enhances Hypoxic Gene Expression and Tumor Growth

Cited by 314 publications

References 59 publications

VHL loss in renal cell carcinoma leads to up-regulation of CUB domain-containing protein 1 to stimulate PKCδ-driven migration

VHL loss in renal cell carcinoma leads to up-regulation of CUB domain-containing protein 1 to stimulate PKCδ-driven migration

Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET

Epigenetic regulation of cancer growth by histone demethylases

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