Epigenetics and metabolism at the crossroads of stress-induced plasticity, stemness and therapeutic resistance in cancer

Menon, Dinoop Ravindran; Hammerlindl, Heinz; Torrano, Joachim; Schaider, Helmut; Fujita, Mayumi

doi:10.7150/thno.42523

Cited by 34 publications

(24 citation statements)

References 220 publications

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“…In addition to telomere shortening in each cell division, senescence can be triggered by multiple genotoxic stresses, e.g., the epigenetic repression of the INK4a / ARF locus, DNA damage, and oxidative stress 37 . Genotoxic chemotherapy and radiation can trigger stress-induced premature senescence in cancer cells during treatment, and this has been demonstrated to affect the therapeutic outcome 38 . Accordingly, a strategy that first evokes senescence and then eliminates senescent cancer cells via the immune system or other mechanisms may provide anticancer benefits.…”

Section: Discussionmentioning

confidence: 99%

Identification of theranostic factors for patients developing metastasis after surgery for early-stage lung adenocarcinoma

Cheng¹,

Chang²,

Lo³

et al. 2021

Theranostics

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Rationale: Lung adenocarcinoma (LUAD) is an aggressive disease with high propensity of metastasis. Among patients with early-stage disease, more than 30% of them may relapse or develop metastasis. There is an unmet medical need to stratify patients with early-stage LUAD according to their risk of relapse/metastasis to guide preventive or therapeutic approaches. In this study, we identified 4 genes that can serve both therapeutic and diagnostic (theranostic) purposes. Methods: Three independent datasets (GEO, TCGA, and KMPlotter) were used to evaluate gene expression profile of patients with LUAD by unbiased screening approach. Upon significant genes uncovered, functional enrichment analysis was carried out. The predictive power of their expression on patient prognosis were evaluated. Once confirmed their theranostic roles by integrated bioinformatics, we further conducted in vitro and in vivo validation. Results: We found that four genes ( ADAM9 , MTHFD2 , RRM2, and SLC2A1) were associated with poor patient outcomes with an increased hazard ratio in LUAD. Knockdown of them, both separately and simultaneously, suppressed lung cancer cell proliferation and migration ability in vitro and prolonged survival time in metastatic tumor mouse models. Moreover, these four biomarkers were found to be overexpressed in tumor tissues from LUAD patients, and the total immunohistochemical staining scores correlated with poor prognosis. Conclusions: These results suggest that these four identified genes could be theranostic biomarkers for stratifying high-risk patients who develop relapse/metastasis in early-stage LUAD. Developing therapeutic approaches for the four biomarkers may benefit early-stage LUAD patients after surgery.

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Section: Discussionmentioning

confidence: 99%

Identification of theranostic factors for patients developing metastasis after surgery for early-stage lung adenocarcinoma

Cheng¹,

Chang²,

Lo³

et al. 2021

Theranostics

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“…The first FDA-approved epidrugs were DNMT and HDAC inhibitors for the treatment of haematological malignancies. 31 , 129 , 130 The experimental and clinical experience gathered over the past years has shown us that: i) these specific but at the same time “globally acting” agents can reprogramme cancer stemness through their interaction with multiple genes and pathways, inhibiting cancer initiation and progression; 129 , 131 ii) long-lasting cancer cell reprogramming, and therefore improved activity, can be achieved at low and less toxic doses of epidrugs; 129 , 132 iii) epidrugs can overcome primary resistance and restore sensitivity of cancer cells to targeted agents and conventional chemotherapeutics; 129 , 133 , 134 iv) epigenetic alterations in cells of the tumour microenvironment (TME), both stromal and immune cells, contribute to carcinogenesis and can be targeted to enhance therapeutic efficacy. Indeed, recent evidence indicates that targeting different epigenetic regulators, including writers (DNMTs and HMTs), readers (BRDs) and erasers (HDACs, KDMs) can increase immune recognition of tumour cells and synergise with immunotherapy.…”

Section: Targeting Epigenetic Mechanisms In Hccmentioning

confidence: 99%

Epigenetics in hepatocellular carcinoma development and therapy: The tip of the iceberg

et al. 2020

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Summary Hepatocellular carcinoma (HCC) is a deadly tumour whose causative agents are generally well known, but whose pathogenesis remains poorly understood. Nevertheless, key genetic alterations are emerging from a heterogeneous molecular landscape, providing information on the tumorigenic process from initiation to progression. Among these molecular alterations, those that affect epigenetic processes are increasingly recognised as contributing to carcinogenesis from preneoplastic stages. The epigenetic machinery regulates gene expression through intertwined and partially characterised circuits involving chromatin remodelers, covalent DNA and histone modifications, and dedicated proteins reading these modifications. In this review, we summarise recent findings on HCC epigenetics, focusing mainly on changes in DNA and histone modifications and their carcinogenic implications. We also discuss the potential drugs that target epigenetic mechanisms for HCC treatment, either alone or in combination with current therapies, including immunotherapies.

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“…Cellular heterogeneity and plasticity are not inherent only to cancer cells but also, to other cellular components of a tumor microenvironment (TME). Stromal compartment has the capacity to promote tumor cell plasticity and proliferation by providing metabolic, and epigenetic, cues [ 28 , 37 , 38 , 39 ]. The onset of senescence facilitates the acquisition of stem cell properties [ 40 ].…”

Section: Cellular Senescence Circumventing Senescence and The Onset Of Cancer Therapy Resistancementioning

confidence: 99%

“…Deregulated NAD + metabolism is a hallmark of many age-related diseases, including cancer [ 19 , 23 , 24 , 25 ]. In response to diverse cellular stresses, both NAD + level, and the adaptability of NAD + metabolism, underlies epigenetically-regulated metabolic reprogramming, commonly leading to the acquisition of phenotypic plasticity and therapy resistance [ 8 , 26 , 27 , 28 ]. The enzyme nicotinamide N-methyltransferase (NNMT), which transfers methyl units from S-adenosyl methionine (SAM) to NAM, has emerged as an important contributor to those processes [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

Nicotinamide N-Methyltransferase in Acquisition of Stem Cell Properties and Therapy Resistance in Cancer

Kujundžić

Prpić

Đaković

et al. 2021

IJMS

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The activity of nicotinamide N-methyltransferase (NNMT) is tightly linked to the maintenance of the nicotinamide adenine dinucleotide (NAD+) level. This enzyme catalyzes methylation of nicotinamide (NAM) into methyl nicotinamide (MNAM), which is either excreted or further metabolized to N1-methyl-2-pyridone-5-carboxamide (2-PY) and H2O2. Enzymatic activity of NNMT is important for the prevention of NAM-mediated inhibition of NAD+-consuming enzymes poly–adenosine -diphosphate (ADP), ribose polymerases (PARPs), and sirtuins (SIRTs). Inappropriately high expression and activity of NNMT, commonly present in various types of cancer, has the potential to disrupt NAD+ homeostasis and cellular methylation potential. Largely overlooked, in the context of cancer, is the inhibitory effect of 2-PY on PARP-1 activity, which abrogates NNMT’s positive effect on cellular NAD+ flux by stalling liberation of NAM and reducing NAD+ synthesis in the salvage pathway. This review describes, and discusses, the mechanisms by which NNMT promotes NAD+ depletion and epigenetic reprogramming, leading to the development of metabolic plasticity, evasion of a major tumor suppressive process of cellular senescence, and acquisition of stem cell properties. All these phenomena are related to therapy resistance and worse clinical outcomes.

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Epigenetics and metabolism at the crossroads of stress-induced plasticity, stemness and therapeutic resistance in cancer

Cited by 34 publications

References 220 publications

Identification of theranostic factors for patients developing metastasis after surgery for early-stage lung adenocarcinoma

Identification of theranostic factors for patients developing metastasis after surgery for early-stage lung adenocarcinoma

Epigenetics in hepatocellular carcinoma development and therapy: The tip of the iceberg

Nicotinamide N-Methyltransferase in Acquisition of Stem Cell Properties and Therapy Resistance in Cancer

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