HIF-1 Inhibits Mitochondrial Biogenesis and Cellular Respiration in VHL-Deficient Renal Cell Carcinoma by Repression of C-MYC Activity

Zhang, Huafeng; Gao, Ping; Fukuda, Ryo; Kumar, Ganesh K.; Krishnamachary, Balaji; Zeller, Karen; Dang, Chi V.; Semenza, Gregg L.

doi:10.1016/j.ccr.2007.04.001

Cited by 788 publications

(755 citation statements)

References 65 publications

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“…Intriguingly, however, HIF and MYC are traditionally considered to have antagonistic effects in the hypoxic cell. Indeed, HIF was found to counteract MYC by various underlying mechanisms including the induction of MXI1, another MYC antagonist, competition with MYC for promoter binding or promoting its proteasomal degradation [45,46]. This paradox may reflect the different models studied so the biological relevance of the miR-210-promoted MYC functions in the regulation of HIF requires further clarification.…”

Section: Transcriptional Feedbackmentioning

confidence: 99%

Understanding complexity in the HIF signaling pathway using systems biology and mathematical modeling

2016

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Section: Transcriptional Feedbackmentioning

confidence: 99%

Understanding complexity in the HIF signaling pathway using systems biology and mathematical modeling

2016

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“…29 Peroxisome proliferators-activated receptor g coactivator 1b is a transcription factor that is regulated by c-Myc and implicated in mitochondrial biogenesis. Study has shown that HIF-a overexpression in a pVHL-deficient renal carcinoma cell line inhibits PGC-1b expression, resulting in decreased mitochondrial DNA content, mitochondrial mass, and oxygen consumption.…”

Section: Hif-a Controls Mitochondrial Biogenesis By Inhibiting C-myc-mentioning

confidence: 99%

“…Study has shown that HIF-a overexpression in a pVHL-deficient renal carcinoma cell line inhibits PGC-1b expression, resulting in decreased mitochondrial DNA content, mitochondrial mass, and oxygen consumption. 29 Both HIF-1a and HIF-2a are involved in the transcriptional repression of PPARGC1B (encoding PGC-1b). In contrast to the direct role of HIF-1a in c-Myc target gene repression (Figure 2b), the HIF-a isoforms inhibit PPARGC1B expression in two indirect ways (Figure 4a).…”

Section: Hif-a Controls Mitochondrial Biogenesis By Inhibiting C-myc-mentioning

confidence: 99%

“…Recent studies, however, have begun to shed new light on these questions by unraveling the intricate role of the protooncoprotein c-Myc in relation to HIF-a in adaptation to the tumor microenvironment. [26][27][28][29] c-Myc plays a central role in a transcription factor network that regulates cellular growth, differentiation, apoptosis, and metabolism. 30,31 It is frequently overexpressed in human cancers because of genetic rearrangements such as gene amplifications and chromosomal translocation.…”

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confidence: 99%

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Carrot and stick: HIF-α engages c-Myc in hypoxic adaptation

Huang

2008

Cell Death Differ

124

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The past decade of research on hypoxic responses has provided a considerable understanding of how cells respond to hypoxic stress at the molecular level, thanks to the identification and molecular cloning of the hypoxia-inducible transcription factor, HIF-1a. Numerous target genes have since been identified to account for various aspects of the hypoxic response, including angiogenesis and glycolysis. Yet, fundamental questions remain regarding the mechanisms by which hypoxia controls cell proliferation, genetic instability, mitochondrial biogenesis, and oxidative respiration in cancer cells. Although the protooncoprotein c-Myc appears to be the diametrical opposite of HIF-1a in most of these processes, recent studies indicate that c-Myc is an integral part of the HIF-a-c-Myc molecular pathway in the hypoxic response. It has been shown that HIF-a engages with Myc by various mechanisms to achieve oxygen homeostasis for cell survival. This article focuses on the intricate roles of cMyc in the hypoxic response, discusses various mechanisms controlling c-Myc activity by HIF-a for the regulation of hypoxiaresponsive genes, and emphasizing the outcome of gene expression apparently dependent upon hypoxic conditions, cellular context, and gene promoter. Solid tumors tend to develop hypoxia (oxygen deprivation), which arises out of the rapid cell proliferation that outstrips the supply of oxygen from the blood vessels. Consequently, tumor hypoxia activates hypoxia-inducible factor (HIF)-1a and HIF-2a, 1,2 two of the well-characterized hypoxia-inducible transcription factors critical for tumor angiogenesis, glycolysis, and metastasis. [3][4][5] Under physiological conditions, hypoxia activates the ubiquitous HIF-1a, whereas HIF-2a expression is more tissue specific. Yet in human cancers of diverse origins, both HIF-1a and HIF-2a, referred to collectively hereinafter as HIF-a, are frequently overexpressed and activated.Hypoxia-inducible factor-a is the regulatory subunit of the HIF heterodimeric complex paired with the aryl hydrocarbon receptor nuclear translocator (ARNT, also known as HIF-1b). 6 They belong to the Per-ARNT-Sim (PAS) superfamily 7 of transcription factors containing basic helix-loop-helix domains (Figure 1a). Whereas PAS domains confer target gene specificity through protein-protein interactions, 8 the oxygendependent degradation domain, unique to HIF-a, mediates oxygen-dependent proteolysis. 9 As such, despite constitutive transcription and translation of the HIF1A and EPAS1 genes (encoding HIF-1a and HIF-2a, respectively), HIF-a protein levels remain low in oxygenated conditions because of proteolysis via the ubiquitin-proteasome pathway. 9-12 HIF-a degradation requires the pVHL-containing E3 ubiquitin ligase, 13-15 which recognizes two hydroxylated proline residues of HIF-a (P402 and P564 in HIF-1a; Figure 1a). [16][17][18] HIFa is hydroxylated by three prolyl hydroxylases, EglN1, EglN2, and EglN3 (better known as PHD2, PHD1, and PHD3, respectively), which sense oxygen tension and transduce oxygen signal...

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“…In addition, it achieves high levels of ROS formation with increased apoptosis rate and severely suppresses cell proliferation and tumor growth. Interestingly, it has been reported that PGC1β knockout mice are protected from carcinogenesis (Bellafante et al ., 2014) and PGC1β expression can be regulated by c‐Myc, a key regulator for cell growth and proliferation (Soucek and Evan, 2010; Zhang et al ., 2007). This indicates that targeting PGC1β or PGC1β expression‐related pathways may be a new approach for antitumor drug development.…”

Section: Discussionmentioning

confidence: 99%

PGC1β regulates multiple myeloma tumor growth through LDHA‐mediated glycolytic metabolism

Zhang

Chen

et al. 2018

Molecular Oncology

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Multiple myeloma (MM) is an incurable hematologic malignancy due to inevitable relapse and chemoresistance development. Our preliminary data show that MM cells express high levels of PGC1β and LDHA. In this study, we investigated the mechanism behind PGC1β‐mediated LDHA expression and its contribution to tumorigenesis, to aid in the development of novel therapeutic approaches for MM. Real‐time PCR and western blotting were first used to evaluate gene expression of PGC1β and LDHA in different MM cells, and then, luciferase reporter assay, chromatin immunoprecipitation, LDHA deletion report vectors, and siRNA techniques were used to investigate the mechanism underlying PGC1β‐induced LDHA expression. Furthermore, knockdown cell lines and lines stably overexpressing PGC1β or LDHA lentivirus were established to evaluate in vitro glycolysis metabolism, mitochondrial function, reactive oxygen species (ROS) formation, and cell proliferation. In addition, in vivo xenograft tumor development studies were performed to investigate the effect of PGC1β or LDHA expression on tumor growth and mouse survival. We found that PGC1β and LDHA are highly expressed in different MM cells and LDHA is upregulated by PGC1β through the PGC1β/RXRβ axis acting on the LDHA promoter. Overexpression of PGC1β or LDHA significantly potentiated glycolysis metabolism with increased cell proliferation and tumor growth. On the other hand, knockdown of PGC1β or LDHA largely suppressed glycolysis metabolism with increased ROS formation and apoptosis rate, in addition to suppressing tumor growth and enhancing mouse survival. This is the first time the mechanism underlying PGC1β‐mediated LDHA expression in multiple myeloma has been identified. We conclude that PGC1β regulates multiple myeloma tumor growth through LDHA‐mediated glycolytic metabolism. Targeting the PGC1β/LDHA pathway may be a novel therapeutic strategy for multiple myeloma treatment.

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HIF-1 Inhibits Mitochondrial Biogenesis and Cellular Respiration in VHL-Deficient Renal Cell Carcinoma by Repression of C-MYC Activity

Cited by 788 publications

References 65 publications

Understanding complexity in the HIF signaling pathway using systems biology and mathematical modeling

Understanding complexity in the HIF signaling pathway using systems biology and mathematical modeling

Carrot and stick: HIF-α engages c-Myc in hypoxic adaptation

PGC1β regulates multiple myeloma tumor growth through LDHA‐mediated glycolytic metabolism

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