HIF activation causes synthetic lethality between the
            <i>VHL</i>
            tumor suppressor and the
            <i>EZH1</i>
            histone methyltransferase

Chakraborty, Abhishek A.; Nakamura, Eijiro; Qi, Jun; Creech, Amanda L.; Jaffe, Jacob D.; Paulk, Joshiawa; Novak, Jesse; Nagulapalli, Kshithija; McBrayer, Samuel K.; Cowley, Glenn S.; Pineda, Javier; Song, Jiuzhou; Wang, Yaoyu E.; Carr, Steven A.; Root, David E.; Signoretti, Sabina; Bradner, James E.; Kaelin, William G.

doi:10.1126/scitranslmed.aal5272

Cited by 37 publications

(23 citation statements)

References 63 publications

(95 reference statements)

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“…Notably, multiple studies have now reported that KDMs are HIF target genes which is particularly relevant in ccRCC in which inactivating mutations of VHL and ensuing HIF stabilization is a common event(64–68). A recent study by Chakraborty et al indicated that VHL-defective RCC cells are dependent on the H3K27 methyltransferase activity of EZH1 for cell survival to counter the HIF-mediated induction of KDMs(69). Multiple studies indicate the importance of EZH2 in RCC phenotypes including in vivo tumor growth and therapy resistance(70, 71).…”

Section: Discussionmentioning

confidence: 99%

Biochemical and Epigenetic Insights into L-2-Hydroxyglutarate, a Potential Therapeutic Target in Renal Cancer

Shelar

Shim

Brinkley

et al. 2018

Clinical Cancer Research

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Elevation of L-2-hydroxylgutarate (L-2-HG) in renal cell carcinoma (RCC) is due in part to reduced expression of L-2-HG dehydrogenase (L2HGDH). However, the contribution of L-2-HG to renal carcinogenesis and insight into the biochemistry and targets of this small molecule remains to be elucidated. Genetic and pharmacologic approaches to modulate L-2-HG levels were assessed for effects on and phenotypes. Metabolomics was used to dissect the biochemical mechanisms that promote L-2-HG accumulation in RCC cells. Transcriptomic analysis was utilized to identify relevant targets of L-2-HG. Finally, bioinformatic and metabolomic analyses were used to assess the L-2-HG/L2HGDH axis as a function of patient outcome and cancer progression. L2HGDH suppresses both cell migration and tumor growth and these effects are mediated by L2HGDH's catalytic activity. Biochemical studies indicate that glutamine is the predominant carbon source for L-2-HG via the activity of malate dehydrogenase 2 (MDH2). Inhibition of the glutamine-MDH2 axis suppresses phenotypes in an L-2-HG-dependent manner. Moreover, growth of RCC cells with basal elevation of L-2-HG is suppressed by glutaminase inhibition. Transcriptomic and functional analyses demonstrate that the histone demethylase KDM6A is a target of L-2-HG in RCC. Finally, increased L-2-HG levels, copy loss, and lower L2HGDH expression are associated with tumor progression and/or worsened prognosis in patients with RCC. Collectively, our studies provide biochemical and mechanistic insight into the biology of this small molecule and provide new opportunities for treating L-2-HG-driven kidney cancers.

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Section: Discussionmentioning

confidence: 99%

Biochemical and Epigenetic Insights into L-2-Hydroxyglutarate, a Potential Therapeutic Target in Renal Cancer

Shelar

Shim

Brinkley

et al. 2018

Clinical Cancer Research

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“…Therefore, it is likely that ccRCC, mostly with VHL loss, would demonstrate a distinctive histone modification. By using a multiplexed and high-resolution quantitative mass spectrometry approach, Chakraborty et al found that ccRCC tumors with VHL loss preferentially upregulate H3K27ac and H3K27me0/me1 levels [ 90 ]. More strikingly, VHL loss leads to the depletion of H3K27me3 due to increased H3K27 demethylase KDM6B activity in ccRCC cells.…”

Section: Vhl and Epigenetic Regulationmentioning

confidence: 99%

“…In addition, Rho-associated kinase 1 (ROCK1) was identified to be synthetically lethal with a VHL loss in an HIF-dependent manner [ 109 ]. The latest research on the selective toxicity of EZH1 inhibitors on VHL-null ccRCC cells also showed their dependency on HIF signaling [ 90 ]. On the other hand, there has been accumulating evidence suggesting that some of the synthetic lethality partners in VHL-loss tumors may not depend on HIF signaling.…”

Section: Targeting Vhl Signaling In Ccrccmentioning

confidence: 99%

VHL and Hypoxia Signaling: Beyond HIF in Cancer

Zhang

2018

Biomedicines

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Von Hippel-Lindau (VHL) is an important tumor suppressor that is lost in the majority of clear cell carcinoma of renal cancer (ccRCC). Its regulatory pathway involves the activity of E3 ligase, which targets hypoxia inducible factor α (including HIF1α and HIF2α) for proteasome degradation. In recent years, emerging literature suggests that VHL also possesses other HIF-independent functions. This review will focus on VHL-mediated signaling pathways involving the latest identified substrates/binding partners, including N-Myc downstream-regulated gene 3 (NDRG3), AKT, and G9a, etc., and their physiological roles in hypoxia signaling and cancer. We will also discuss the crosstalk between VHL and NF-κB signaling. Lastly, we will review the latest findings on targeting VHL signaling in cancer.

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“…In a study using a database of human acute myeloid leukemia (AML) cell lines, a genome-wide CRISPR-based screen revealed PREX1 as an AML-specific activator of MAPK signaling in RAS processing [62]. The synthetic lethality of the von Hippel-Lindau (VHL) tumor suppressor gene and HIF activity correlated with histone methyltransferase EZH1 function were reported in renal cancer with CRISPR-Cas9 system elimination [63]. As various approaches have been utilized in other cancer types, it is desirable to further promote studies using the latest technology, including CRISPR-Cas9 and other modalities.…”

Section: Discovering Synthetic Lethal Interaction In Lung Cancermentioning

confidence: 99%

Synthetic Lethality in Lung Cancer—From the Perspective of Cancer Genomics

Shimomura

Yamamoto²,

Ochiya

2019

Medicines

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Cancer is a genetic disease, and this concept is now widely exploited by both scientists and clinicians to develop new genotype-selective anticancer therapeutics. Although the quest of cancer genomics is in its dawn, recognition of the widespread applicability of genetic interactions with biological processes of tumorigenesis is propelling research throughout academic fields. Lung cancer is the most common cause of cancer death worldwide, with an estimated 1.6 million deaths each year. Despite the development of targeted therapies that inhibit oncogenic mutations of lung cancer cases, continued research into new therapeutic approaches is required for untreatable lung cancer patients, and the development of therapeutic modalities has proven elusive. The “synthetic lethal” approach holds the promise of delivering a therapeutic regimen that preferentially targets malignant cells while sparing normal cells. We highlight the potential challenges in synthetic lethal anticancer therapeutics that target untreatable genetic alterations in lung cancer. We also discuss both challenges and opportunities regarding the application of new synthetic lethal interactions in lung cancer.

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HIF activation causes synthetic lethality between the VHL tumor suppressor and the EZH1 histone methyltransferase

Cited by 37 publications

References 63 publications

Biochemical and Epigenetic Insights into L-2-Hydroxyglutarate, a Potential Therapeutic Target in Renal Cancer

Biochemical and Epigenetic Insights into L-2-Hydroxyglutarate, a Potential Therapeutic Target in Renal Cancer

VHL and Hypoxia Signaling: Beyond HIF in Cancer

Synthetic Lethality in Lung Cancer—From the Perspective of Cancer Genomics

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