Tumour initiation and progression requires the metabolic reprogramming of cancer cells. Cancer cells autonomously alter their flux through various metabolic pathways in order to meet the increased bioenergetic and biosynthetic demand as well as mitigate oxidative stress required for cancer cell proliferation and survival. Cancer driver mutations coupled with environmental nutrient availability control flux through these metabolic pathways. Metabolites, when aberrantly accumulated, can also promote tumorigenesis. The development and application of new technologies over the last few decades has not only revealed the heterogeneity and plasticity of tumours but also allowed us to uncover new metabolic pathways involved in supporting tumour growth. The tumour microenvironment (TME), which can be depleted of certain nutrients, forces cancer cells to adapt by inducing nutrient scavenging mechanisms to sustain cancer cell proliferation. There is growing appreciation that the metabolism of cell types other than cancer cells within the TME, including endothelial cells, fibroblasts and immune cells, can modulate tumour progression. Because metastases are a major cause of death of patients with cancer, efforts are underway to understand how metabolism is harnessed by metastatic cells. Additionally, there is a new interest in exploiting cancer genetic analysis for patient stratification and/or dietary interventions in combination with therapies that target metabolism. In this Perspective, we highlight these main themes that are currently under investigation in the context of in vivo tumour metabolism, specifically emphasizing questions that remain unanswered.

Cancer metabolism: looking forward

Most (if not all) tumors emerge and progress under a strong evolutionary pressure imposed by trophic, metabolic, immunological, and therapeutic factors The relative impact of these factors on tumor evolution changes over space and time, ultimately favoring the establishment of a neoplastic microenvironment that exhibits considerable genetic, phenotypic, and behavioral heterogeneity in all its components Here, we discuss the main sources of intratumoral heterogeneity and its impact on the natural history of the disease, including sensitivity to treatment, as we delineate potential strategies to target such a detrimental feature of aggressive malignancies The many levels of heterogeneity within tumors dictate their response to therapy and should be considered in future therapeutic regimes

Intratumoral heterogeneity in cancer progression and response to immunotherapy.

Metabolic rewiring and epigenetic remodeling, which are closely linked and reciprocally regulate each other, are among the well-known cancer hallmarks. Recent evidence suggests that many metabolites serve as substrates or cofactors of chromatin-modifying enzymes as a consequence of the translocation or spatial regionalization of enzymes or metabolites. Various metabolic alterations and epigenetic modifications also reportedly drive immune escape or impede immunosurveillance within certain contexts, playing important roles in tumor progression. In this review, we focus on how metabolic reprogramming of tumor cells and immune cells reshapes epigenetic alterations, in particular the acetylation and methylation of histone proteins and DNA. We also discuss other eminent metabolic modifications such as, succinylation, hydroxybutyrylation, and lactylation, and update the current advances in metabolism- and epigenetic modification-based therapeutic prospects in cancer.

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Metabolic reprogramming and epigenetic modifications on the path to cancer.

Molecular inputs to chromatin via cellular metabolism are modifiers of the epigenome. These inputs — which include both nutrient availability as a result of diet and growth factor signalling — are implicated in linking the environment to the maintenance of cellular homeostasis and cell identity. Recent studies have demonstrated that these inputs are much broader than had previously been known, encompassing metabolism from a wide variety of sources, including alcohol and microbiotal metabolism. These factors modify DNA and histones and exert specific effects on cell biology, systemic physiology and pathology. In this Review, we discuss the nature of these molecular networks, highlight their role in mediating cellular responses and explore their modifiability through dietary and pharmacological interventions. Various cellular metabolites provide the chemical moieties for DNA and histone modifications, resulting in a complex interplay between metabolism and epigenetics. In this Review, Dai, Ramesh and Locasale discuss the metabolic regulation of diverse types of chromatin modifications and the functional consequences of these modifications at the molecular, cellular and organismal levels, as well as influences from diet and microbiota.

The evolving metabolic landscape of chromatin biology and epigenetics.

Developing novel targeted anticancer therapies is a major goal of current research. The use of poly(ADP-ribose) polymerase (PARP) inhibitors in patients with homologous recombination-deficient tumours provides one of the best examples of a targeted therapy that has been successfully translated into the clinic. The success of this approach has so far led to the approval of four different PARP inhibitors for the treatment of several types of cancers and a total of seven different compounds are currently under clinical investigation for various indications. Clinical trials have demonstrated promising response rates among patients receiving PARP inhibitors, although the majority will inevitably develop resistance. Preclinical and clinical data have revealed multiple mechanisms of resistance and current efforts are focused on developing strategies to address this challenge. In this Review, we summarize the diverse processes underlying resistance to PARP inhibitors and discuss the potential strategies that might overcome these mechanisms such as combinations with chemotherapies, targeting the acquired vulnerabilities associated with resistance to PARP inhibitors or suppressing genomic instability. Poly(ADP-ribose) polymerase (PARP) inhibitors are approved for patients with several forms of cancer, predominantly those harbouring loss-of-function BRCA1/2 mutations or other homologous recombination defects. Nonetheless, most patients receiving PARP inhibitors will ultimately develop resistance to PARP inhibitors, resulting in disease progression. In this Review, the authors describe the mechanisms of resistance to PARP inhibitors and discuss the potential treatment strategies that might overcome these effects.

Understanding and overcoming resistance to PARP inhibitors in cancer therapy.

Deregulation of metabolism and disruption of genome integrity are hallmarks of cancer1. Increased levels of the metabolites 2-hydroxyglutarate, succinate and fumarate occur in human malignancies owing to somatic mutations in the isocitrate dehydrogenase-1 or -2 (IDH1 or IDH2) genes, or germline mutations in the fumarate hydratase (FH) and succinate dehydrogenase genes (SDHA, SDHB, SDHC and SDHD), respectively2-4. Recent work has made an unexpected connection between these metabolites and DNA repair by showing that they suppress the pathway of homology-dependent repair (HDR)5,6 and confer an exquisite sensitivity to inhibitors of poly (ADP-ribose) polymerase (PARP) that are being tested in clinical trials. However, the mechanism by which these oncometabolites inhibit HDR remains poorly understood. Here we determine the pathway by which these metabolites disrupt DNA repair. We show that oncometabolite-induced inhibition of the lysine demethylase KDM4B results in aberrant hypermethylation of histone 3 lysine 9 (H3K9) at loci surrounding DNA breaks, masking a local H3K9 trimethylation signal that is essential for the proper execution of HDR. Consequently, recruitment of TIP60 and ATM, two key proximal HDR factors, is substantially impaired at DNA breaks, with reduced end resection and diminished recruitment of downstream repair factors. These findings provide a mechanistic basis for oncometabolite-induced HDR suppression and may guide effective strategies to exploit these defects for therapeutic gain.

Oncometabolites suppress DNA repair by disrupting local chromatin signalling


 The cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway, a component of the innate immune system, functions to detect the presence of cytosolic DNA, and STING signaling is necessary for the anti-cancer immune response. However, STING expression is suppressed or lost in the majority of cancers, which correlates with poor survival in cancer patients. Hypoxia is a key feature of solid tumors that adversely affects prognosis by altering gene expression, creating an immunosuppressive tumor microenvironment, promoting genome instability, and hampering therapy responses. In this study, we found that that prolonged moderate hypoxia induces downregulation of STING expression in multiple cancer cell lines, causing decreased STING pathway activation after treatment with a STING agonist, or with DNA damaging chemotherapy. Mechanically, we found that hypoxia suppressed histone 3 lysine 4 (H3K4) methylation at the STING promoter based on chromatin immunoprecipitation (ChIP) assays in H1975 cells, a non-small cell lung cancer cell line, and knockdown of the H3K4 demethylases, KDM5A or KDM1A, prior to hypoxic exposure prevented hypoxia-induced down-regulation of STING expression. Moreover, decreased STING expression in hypoxic cells was reversed by treatment with the DNA methyltransferase inhibitor, 5-aza-2′-deoxycytidine. Next, we found that prolonged hypoxia increased both D-2-hydroxyglutarate (D-2-HG) and L-2-HG levels in H1975 cells, and that 2-HG treatment, by itself, decreased STING expression under normoxic conditions in H1975 cells. These findings are consistent with analysis of TCGA data showing that STING expression at the mRNA level is reduced in malignancies with mutations in isocitrate dehydrogenase 1 (IDH1) which causes elevated D-2-HG. Furthermore, we found that hypoxia increased Branched Chain Amino Acid Transaminase 1 (BCAT1) expression, and overexpression of BCAT1 accelerated STING downregulation in hypoxic condition. Functionally, expression of interferon (IFN)-stimulated genes (ISGs), CCL5 and interferon-β, was low in hypoxic H1975 cells compared to normoxic cells after treatment with poly(dA:dT), a small molecule STING agonist, and doxorubicin. Immunogenic cell death (ICD) was also reduced in hypoxic H1975 cells. In summary, the results suggest that hypoxia suppresses STING expression through epigenetic regulation, leading to STING silencing, and that this process synergizes with oncometabolites. The decreased STING caused by hypoxia further causes reduction of innate immune responses in cancer cells. Our study provides new understanding of the underlying mechanisms for STING silencing, which will help not only to study cancer immunity but also to develop novel therapeutic strategies.
 Citation Format: Yuhong Lu, Annali Yurkevicz, Yanfeng Liu, Jonathan Dow, Peter M. Glazer. Hypoxia induces down-regulation of stimulator of interferon genes (STING) that is synergized with oncometabolites [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1263.

Abstract 1263: Hypoxia induces down-regulation of stimulator of interferon genes (STING) that is synergized with oncometabolites

Exploitation of DNA repair defects has enabled major advances in treating specific cancers. Recent work discovered that the oncometabolite 2-hydroxyglutarate (2-HG), produced by neomorphic isocitrate dehydrogenase 1/2 (IDH1/2) mutations, confers a homology-directed repair (HDR) defect through 2-HG–induced histone hypermethylation masking HDR signaling. Here, we report that IDH1-mutant cancer cells are profoundly sensitive to the histone deacetylase inhibitor (HDACi) vorinostat, by further suppressing the residual HDR in 2-HG–producing cells. Vorinostat downregulates repair factors BRCA1 and RAD51 via disrupted E2F-factor regulation, causing increased DNA double-strand breaks, reduced DNA repair factor foci, and functional HDR deficiency even beyond 2-HG9s effects. This results in greater cell death of IDH1-mutant cells and confers synergy with radiation and PARPi, both against cells in culture and patient-derived tumor xenografts. Our work identifies HDACi9s utility against IDH1-mutant cancers, and presents IDH1/2 mutations as potential biomarkers to guide trials testing HDACi in gliomas and other malignancies. Implications: IDH1-mutant cells show profound vulnerability to HDACi treatment, alone and with PARPi and radiation, via HDR suppression, presenting IDH1/2 mutations as biomarkers for HDACi use in gliomas and other malignancies.

Vulnerability of IDH1-Mutant Cancers to Histone Deacetylase Inhibition via Orthogonal Suppression of DNA Repair.

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Oncometabolites suppress DNA repair by disrupting local chromatin signalling

Abstract 1263: Hypoxia induces down-regulation of stimulator of interferon genes (STING) that is synergized with oncometabolites

Vulnerability of IDH1-Mutant Cancers to Histone Deacetylase Inhibition via Orthogonal Suppression of DNA Repair.