HDAC inhibitors elicit metabolic reprogramming by targeting super-enhancers in glioblastoma models

Nguyen, Trang; Zhang, Yiru; Shang, Enyuan; Shu, Chang; Torrini, Consuelo; Zhao, Junfei; Bianchetti, Elena; Mela, Angeliki; Humala, Nelson; Mahajan, Aayushi; Harmanci, Arif; Lei, Zhengdeng; Maienschein‐Cline, Mark; Quinzii, Catarina M.; Westhoff, Mike‐Andrew; Karpel‐Massler, Georg; Bruce, Jeffrey N.; Canoll, Peter; Siegelin, Markus D.

doi:10.1172/jci129049

Cited by 134 publications

(132 citation statements)

References 45 publications

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“…Based on the literature and our own work, the integrated stress response is known to be related to metabolism and our earlier work demonstrated a role for gamitrinib as well as panobinostat in GBM metabolism [ 13 , 18 ]. Given that these effects are contrary to tumor cell respiration (i.e., panobinostat increases, whereas gamitrinib suppresses the oxygen consumption rate (OCR)) through disruption of the complex II of the respiratory chain (SDH), we hypothesized that gamitrinib might suppress panobinostat mediated increase in oxygen consumption rate.…”

Section: Resultsmentioning

confidence: 99%

“…Following transfection, protein expression of both SDHA and SDHB was assessed by protein capillary electrophoresis, demonstrating that TRAP1 silencing sufficed to suppress these two proteins that are associated with complex two of the respiratory chain ( Figure 5 E). Previous findings from our group demonstrated that panobinostat up-regulated SDHA and SDHB following acute and chronic treatment with panobinostat and that the up-regulation is mediated on a transcriptional level [ 13 ]. Given that HDAC inhibitors affect the post-translational status of histones and histones regulate the accessibility of the chromatin we assessed the status of H3K27ac, H3K27me3 and RNA polymerase II (Rpb1) binding to the SDHA and SDHB locus by chromatin immunoprecipitation coupled with next generation sequencing of vehicle or panobinostat treated cells ( Figure 5 F).…”

Section: Resultsmentioning

confidence: 99%

“…Notwithstanding these techniques, tumor cell metabolism has received significant attention in the field as well in light of the notion that tumor cells develop distinct features that will allow them to grow relentlessly. One of these metabolic effects is the Warburg effect [ 27 ] and our recent work demonstrated that global and selective HDAC inhibitor disrupt this phenomenon by targeting super-enhancers in genes, such as HK2, GAPDH and ENO1 [ 13 ]. Following treatment with HDAC inhibitors we noted incomplete cell killing and the surviving GBM cells displayed a reduced glycolytic activity and in order to maintain survival they facilitated tumor respiration, which in the present and earlier work we were able to link to up-regulation of respiratory complexes [ 13 ].…”

Section: Discussionmentioning

confidence: 99%

“…However, to date, these molecules have fallen short of expectation in the context of glioblastoma treatment [ 12 ], emphasizing the need for combination treatments. Recent findings from our lab have highlighted that in GBM model systems HDAC inhibitors block glycolysis and in turn activate oxidative phosphorylation fueled by fatty acid oxidation to counteract cell death and inhibition of proliferation [ 13 ]. Therefore, blocking the electron transport chain by TRAP1 antagonist may likely enhance the killing effect of FDA approved HDAC inhibitors in GBM cells.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of HDAC1/2 Along with TRAP1 Causes Synthetic Lethality in Glioblastoma Model Systems

Nguyen

Zhang

Shang

et al. 2020

Cells

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The heterogeneity of glioblastomas, the most common primary malignant brain tumor, remains a significant challenge for the treatment of these devastating tumors. Therefore, novel combination treatments are warranted. Here, we showed that the combined inhibition of TRAP1 by gamitrinib and histone deacetylases (HDAC1/HDAC2) through romidepsin or panobinostat caused synergistic growth reduction of established and patient-derived xenograft (PDX) glioblastoma cells. This was accompanied by enhanced cell death with features of apoptosis and activation of caspases. The combination treatment modulated the levels of pro- and anti-apoptotic Bcl-2 family members, including BIM and Noxa, Mcl-1, Bcl-2 and Bcl-xL. Silencing of Noxa, BAK and BAX attenuated the effects of the combination treatment. At the metabolic level, the combination treatment led to an enhanced reduction of oxygen consumption rate and elicited an unfolded stress response. Finally, we tested whether the combination treatment of gamitrinib and panobinostat exerted therapeutic efficacy in PDX models of glioblastoma (GBM) in mice. While single treatments led to mild to moderate reduction in tumor growth, the combination treatment suppressed tumor growth significantly stronger than single treatments without induction of toxicity. Taken together, we have provided evidence that simultaneous targeting of TRAP1 and HDAC1/2 is efficacious to reduce tumor growth in model systems of glioblastoma.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Inhibition of HDAC1/2 Along with TRAP1 Causes Synthetic Lethality in Glioblastoma Model Systems

Nguyen

Zhang

Shang

et al. 2020

Cells

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“…The reprogramming of energy metabolism is a pivotal step of tumor disease [33] . Warburg effect was known as an important feature of the metabolism in tumor and a method of ATP generation through oxidative phosphorylation occurring even under normal oxygen concentrations [34] . The key role of Fbw7 for tumor metabolism has recently received increased attention.…”

Section: Discussionmentioning

confidence: 99%

Fbw7 Inhibits the Progression of Activated B-cell Like Diffuse Large B-cell Lymphoma by Targeting the Positive Feedback Loop of the LDHA/lactate/miR-223 Axis

Yao¹,

Guo²,

Zhang³

et al. 2020

Preprint

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Background: F-box and WD repeat domain-containing 7 (Fbw7) is an ubiquitin ligase and tumor suppressor which targets a variety of oncogenic proteins for proteolysis. We previously reported that Fbw7 regulates apoptosis in diffuse large B-cell lymphoma (DLBCL) through Fbw7-mediated ubiquitination of Stat3. However, the mechanism by Fbw7-mediated tumor metabolism remains undefined. We examined the function of Fbw7 for tumor metabolism and progression in DLBCL.Methods: The effect of Fbw7 overexpression on Lactate Dehydrogenase A (LDHA)-related tumor metabolism was explored in activated B-cell (ABC) like DLBCL. And Fbw7-mediated expression of LDHA in DLBCL was detected by immunoprecipitation for protein interaction, ubiquitination assay, western blotting and mRNA qualitative analyses. In vitro and in vivo studies were done to measure the function of the Fbw7-mediated LDHA/lactate/miR-223 axis in DLBCL progression.Results: We demonstrated that the ubiquitin-ligase Fbw7 played a key role in LDHA-related metabolism. As LDHA and its catalytic lactate were critical for tumor growth and progression in ABC-DLBCL, our results demonstrated that Fbw7 could interact with LDHA to trigger its ubiquitination and degradation, and lactate negatively regulated Fbw7 via inducing the expression of miR-223, which targeted Fbw7 3’-UTR to inhibit its expression. In vivo and in vitro studies revealed that miR-223 promoted tumor growth and that the effects of miR-223 on tumor growth were primarily related to the inhibition of Fbw7-mediated LDHA’s ubiquitination. Conclusions: Our study uncovers a positive functional loop consisting of a Fbw7-mediated LDHA/lactate/miR-223 axis, which may support the future ABC-DLBCL therapy by targeting LDHA-related inhibition.

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Crosstalk between metabolic reprogramming and epigenetics in cancer: updates on mechanisms and therapeutic opportunities

Jia

et al. 2022

Cancer Communications

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Reversible, spatial, and temporal regulation of metabolic reprogramming and epigenetic homeostasis are prominent hallmarks of carcinogenesis. Cancer cells reprogram their metabolism to meet the high bioenergetic and biosynthetic demands for vigorous proliferation. Epigenetic dysregulation is a common feature of human cancers, which contributes to tumorigenesis and maintenance of the malignant phenotypes by regulating gene expression. The epigenome is sensitive to metabolic changes. Metabolism produces various metabolites that are substrates, cofactors, or inhibitors of epigenetic enzymes. Alterations in metabolic pathways and fluctuations in intermediate metabolites convey information regarding the intracellular metabolic status into the nucleus by modulating the activity of epigenetic enzymes and thus remodeling the epigenetic landscape, inducing transcriptional responses to heterogeneous metabolic requirements. Cancer metabolism is regulated by epigenetic machinery at both transcriptional and post‐transcriptional levels. Epigenetic modifiers, chromatin remodelers and non‐coding RNAs are integral contributors to the regulatory networks involved in cancer metabolism, facilitating malignant transformation. However, the significance of the close connection between metabolism and epigenetics in the context of cancer has not been fully deciphered. Thus, it will be constructive to summarize and update the emerging new evidence supporting this bidirectional crosstalk and deeply assess how the crosstalk between metabolic reprogramming and epigenetic abnormalities could be exploited to optimize treatment paradigms and establish new therapeutic options. In this review, we summarize the central mechanisms by which epigenetics and metabolism reciprocally modulate each other in cancer and elaborate upon and update the major contributions of the interplays between epigenetic aberrations and metabolic rewiring to cancer initiation and development. Finally, we highlight the potential therapeutic opportunities for hematological malignancies and solid tumors by targeting this epigenetic‐metabolic circuit. In summary, we endeavored to depict the current understanding of the coordination between these fundamental abnormalities more comprehensively and provide new perspectives for utilizing metabolic and epigenetic targets for cancer treatment.

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HDAC inhibitors elicit metabolic reprogramming by targeting super-enhancers in glioblastoma models

Cited by 134 publications

References 45 publications

Inhibition of HDAC1/2 Along with TRAP1 Causes Synthetic Lethality in Glioblastoma Model Systems

Inhibition of HDAC1/2 Along with TRAP1 Causes Synthetic Lethality in Glioblastoma Model Systems

Fbw7 Inhibits the Progression of Activated B-cell Like Diffuse Large B-cell Lymphoma by Targeting the Positive Feedback Loop of the LDHA/lactate/miR-223 Axis

Crosstalk between metabolic reprogramming and epigenetics in cancer: updates on mechanisms and therapeutic opportunities

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