Elsevier

Seminars in Cancer Biology

Volume 83, August 2022, Pages 399-412
Seminars in Cancer Biology

Inflammasomes in cancer: Effect of epigenetic and autophagic modulations

https://doi.org/10.1016/j.semcancer.2020.09.013Get rights and content

Abstract

Tumour-promoting inflammation is a critical hallmark in cancer development, and inflammasomes are well-known regulators of inflammatory processes within the tumour microenvironment. Different inflammasome components along with the adaptor, apoptosis-associated speck-like protein containing caspase activation and recruitment domain (ASC), and the effector, caspase-1, have a significant influence on tumorigenesis but in a tissue-specific and stage-dependent manner. The downstream products of inflammasome activation, that is the proinflammatory cytokines such as IL-1β and IL-18, regulate tissue homeostasis and induce antitumour immune responses, but in contrast, they can also favour cancer growth and proliferation by directing various oncogenic signalling pathways in cancer cells. Moreover, different epigenetic mechanisms, including DNA methylation, histone modification and noncoding RNAs, control inflammasomes and their components by regulating gene expression during cancer progression. Furthermore, autophagy, a master controller of cellular homeostasis, targets inflammasome-induced carcinogenesis by maintaining cellular homeostasis and removing potential cancer risk factors that promote inflammasome activation in support of tumorigenesis. Here, in this review, we summarize the effect of inflammasome activation in cancers and discuss the role of epigenetic and autophagic regulatory mechanisms in controlling inflammasomes. A proper understanding of the interactions among these key processes will be useful for developing novel therapeutic regimens for targeting inflammasomes in cancer.

Introduction

Inflammation plays a crucial role in cancer and is involved in tumour initiation, malignant transformation, invasion and metastasis [1], [2]. Tumour-promoting inflammation is also regarded as a hallmark of cancer, and it has a vital role in the formation and maintenance of tumour architecture [3]. The cytokines and chemokines produced by cancer cells as well as non-cancer and immune cells have pro-tumour and antitumour roles, and their complex interaction and signalling within the tumour microenvironment determines the fate of cancer [4]. The pro-inflammatory cytokines produced as an outcome of inflammatory processes lead to immunosuppression, promotion of angiogenesis, invasion and metastasis [5]. Cytokines such as TNF-α and IL-1 aggravate angiogenesis via upregulation of vascular endothelial growth factor (VEGF) by modulating various chemokine receptor signalling pathways and the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway [6]. Inflammasomes are multiprotein complexes that respond to well-known markers of both exogenous and endogenous cellular stress. They identify different cellular stressors through specialized receptors, and lead to cleavage and subsequent activation of IL-1β and IL-18 and induction of inflammatory pyroptotic cell death by regulating the activation of caspase-1 [7]. The role of inflammasomes has been well characterized in various inflammatory diseases, infections, and autoimmune conditions. However, in the case of cancer, the role of inflammasomes has remained controversial for years. This is because of the differential roles played by these protein complexes in different cancer models. Inflammasomes and their components have been well reported to be involved in the progression of cancer, including lung, oral and head and neck squamous cell carcinomas [8], [9], [10], [11]. However, contrasting reports also indicate the tumour-suppressive role of inflammasomes in the development and progression of some cancers, such as colorectal cancer [12]. Hence, the complex role of inflammasomes in oncology demands closer attention.

Epigenetic events such as DNA methylation, histone modification and posttranscriptional alteration of gene expression through noncoding RNAs have important roles during cancer progression [13], [14], [15]. Furthermore, epigenetic regulation modulates the expression of genes encoding inflammasome components during various diseases [16]. Here, we discuss the epigenetic events regulating the expression of inflammasome components and their respective roles in cancer. In addition, we analyse the interconnection between autophagy and inflammasomes from a cancer perspective. Autophagy is a conserved catabolic process that helps in the maintenance of cellular homeostasis in a variety of stress conditions and has a promising role in diverse diseases [17]. Autophagy also acts as a regulator during inflammation, checking hyperactivation of inflammatory responses and inducing a steady response [18]. However, the role of autophagy in cancer is controversial due to its stage-specific behaviour during cancer progression [19], [20]. Moreover, both the inflammasome and autophagy have critical roles in the recognition and eradication of cellular stresses and the protection of cells and their normal physiological processes. Recent studies also depict autophagy as a key factor regulating inflammasome activation and its consequences in the tumour microenvironment. Interestingly, increasing studies on various phytotherapeutic approaches to modulate autophagic regulation of inflammasomes from a cancer perspective have emerged recently. This review provides a comprehensive summary of the epigenetic and autophagic regulatory mechanisms of inflammasome activation during cancer initiation, progression and malignant transformation and is useful for exploring new therapeutic targets in cancer.

Section snippets

Inflammasomes: structure, activation and consequences

Inflammasomes are a type of protein complex that play an essential role in the maintenance of cellular homeostasis during stress by regulating immunity and inflammation. The stress may be tissue damage, metabolic imbalance, pathogen invasion or any type of infection. These multimeric protein complexes generally consist of three parts: a sensor, an adaptor (that is, apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC)) and an effector (that is,

Role of inflammasomes in tumour progression

Deregulated inflammatory responses have a significant influence on tumour initiation and progression by providing a continuous supply of growth factors for limitless replication and DNA damaging agents for permanent genomic instability [40]. Transcription factors such as NF-κB and STAT3, when activated by extrinsic or intrinsic inducers, lead to activation and accumulation of several factors supporting aberrant inflammation, immune suppression and tumour promotion [41], [42], [43], [44].

Tumour-suppressive role of NLR family inflammasomes

The tumour-suppressive role of inflammasomes has been widely explored in colorectal cancer models. Mice lacking NLRP3 or caspase-1 are more susceptible to azoxymethane (AOM) and dextran sodium sulfate (DSS) induced colitis-associated cancer (CAC) than wild-type mice, suggesting a protective role of NLRP3 inflammasomes in CAC. In these cases, increased cancer progression correlates with a decrease in IL-18 and IL-1β levels within the tumour microenvironment [72]. In colorectal cancer, decreased

Epigenetic regulation of inflammasome components and their role in cancer

Epigenetics in general refers to stable inheritable alterations in gene expression without changes to the DNA sequence. Major epigenetic changes, including DNA methylation, modification of histones and posttranscriptional modification through noncoding RNAs, have been well studied for their vital role in regulating the expression of key genes during cancer progression. DNA methylation is the addition of a methyl group to the cytosine residue at the C5 position mostly within CpG dinucleotides by

Autophagy and inflammasomes: what is the connection?

Autophagy is an evolutionarily conserved catabolic process for the degradation of damaged cytoplasmic parts and dysfunctional organelles in a lysosome-dependent manner. The vital role of autophagy in the maintenance of cellular homeostasis is evident in a variety of stress conditions [118]. The complete autophagic process of cellular recycling can be divided into four steps: phagophore initiation, elongation and maturation, autophagosome formation and cargo degradation. Initiation of the

Epigenetic reprogramming and autophagy modulation to influence inflammasomes in cancer and possible therapy

Inflammasome activation has a multifaceted impact on cancer progression, and epigenetic and autophagic modulation of inflammasomes could have potential implications in cancer treatment. Aberrant epigenetic modifications are associated with the silencing of genes encoding various inflammasome components. For example, promoter hypermethylation of the ASC gene is a useful marker for prostate cancer carcinogenesis, and pharmacological demethylation of ASC could be a novel therapeutic intervention

Conclusion and perspective

The role of the inflammasome in cancer is questionable. On the one hand, inflammasome activation contributes to cancer growth, progression and metastasis in lung, breast, skin, oral, and head and neck cancers by inducing tumour-promoting inflammation; on the other hand, inflammasomes have been reported to restrict cancer cell survival by promoting pyroptotic cell death, bringing an effective immune response and maintaining proper tissue homeostasis in inflammation-associated colorectal cancers.

Declaration of Competing Interest

The authors report no declarations of interest.

Acknowledgements

Research support was partly provided by the Department of Biotechnology [BT/PR23304/MED/30/1823/2017], Ministry of Science and Technology, Government of India. SRM acknowledge Department of Biotechnology, Government of India for providing fellowship.

References (149)

  • P.K. Raut et al.

    Growth of breast cancer cells by leptin is mediated via activation of the inflammasome: critical roles of estrogen receptor signaling and reactive oxygen species production

    Biochem. Pharmacol.

    (2019)
  • C.F. Huang et al.

    NLRP3 inflammasome activation promotes inflammation-induced carcinogenesis in head and neck squamous cell carcinoma

    J. Exp. Clin. Cancer Res.

    (2017)
  • M. Okamoto et al.

    Constitutively active inflammasome in human melanoma cells mediating autoinflammation via caspase-1 processing and secretion of interleukin-1beta

    J. Biol. Chem.

    (2010)
  • Y. Nakamura et al.

    Overexpression of absent in melanoma 2 in oral squamous cell carcinoma contributes to tumor progression

    Biochem. Biophys. Res. Commun.

    (2019)
  • E.A. Perez-Yepez et al.

    A novel beta-catenin signaling pathway activated by IL-1beta leads to the onset of epithelial-mesenchymal transition in breast cancer cells

    Cancer Lett.

    (2014)
  • J. Dupaul-Chicoine et al.

    The Nlrp3 inflammasome suppresses colorectal Cancer Metastatic growth in the liver by promoting natural killer cell tumoricidal activity

    Immunity

    (2015)
  • Q. Wei et al.

    Deregulation of the NLRP3 inflammasome in hepatic parenchymal cells during liver cancer progression

    Lab. Investig.

    (2014)
  • I.C. Allen et al.

    NLRP12 suppresses colon inflammation and tumorigenesis through the negative regulation of noncanonical NF-kappaB signaling

    Immunity

    (2012)
  • S.M. Man et al.

    Critical role for the DNA sensor AIM2 in stem cell proliferation and cancer

    Cell

    (2015)
  • J. Chen et al.

    AIM2 regulates viability and apoptosis in human colorectal cancer cells via the PI3K/Akt pathway

    Onco. Ther.

    (2017)
  • D. Chai et al.

    AIM2 is a potential therapeutic target in human renal carcinoma and suppresses its invasion and metastasis via enhancing autophagy induction

    Exp. Cell Res.

    (2018)
  • W. Liu et al.

    Dual role of apoptosis-associated speck-like protein containing a CARD (ASC) in tumorigenesis of human melanoma

    J. Invest. Dermatol.

    (2013)
  • M. Berdasco et al.

    Aberrant epigenetic landscape in cancer: how cellular identity Goes Awry

    Dev. Cell

    (2010)
  • S.K. Patra

    Ras regulation of DNA-methylation and cancer

    Exp. Cell Res.

    (2008)
  • B. Zhang et al.

    microRNAs as oncogenes and tumor suppressors

    Dev. Biol.

    (2007)
  • C.C. Liu et al.

    Upregulation of NLRP3 via STAT3-dependent histone acetylation contributes to painful neuropathy induced by bortezomib

    Exp. Neurol.

    (2018)
  • T. Yokoyama et al.

    Methylation of ASC/TMS1, a proapoptotic gene responsible for activating procaspase-1, in human colorectal cancer

    Cancer Lett.

    (2003)
  • L.M. Coussens et al.

    Inflammation and cancer

    Nature

    (2002)
  • L. Shi et al.

    Targeting roles of inflammatory microenvironment in lung cancer and metastasis

    Cancer Metastasis Rev.

    (2015)
  • A. Mantovani et al.

    Cancer-related inflammation

    Nature

    (2008)
  • Q. Zhang et al.

    Resolution of cancer-promoting inflammation: a new approach for anticancer therapy

    Front. Immunol.

    (2017)
  • D. Sharma et al.

    The cell biology of inflammasomes: mechanisms of inflammasome activation and regulation

    J. Cell Biol.

    (2016)
  • M. Qi et al.
    (2020)
  • H. Wang et al.

    NLRP3 promotes tumor growth and metastasis in human oral squamous cell carcinoma

    BMC Cancer

    (2018)
  • M.H. Zaki et al.

    IL-18 production downstream of the Nlrp3 inflammasome confers protection against colorectal tumor formation

    J. Immunol.

    (2010)
  • S. Sharma et al.

    Epigenetics in cancer

    Carcinogenesis

    (2010)
  • S.K. Patra et al.

    Demethylation of (Cytosine-5-C-methyl) DNA and regulation of transcription in the epigenetic pathways of cancer development

    Cancer Metastasis Rev.

    (2008)
  • R. Vento-Tormo et al.

    DNA demethylation of inflammasome-associated genes is enhanced in patients with cryopyrin-associated periodic syndromes

    J. Allergy Clin. Immunol.

    (2017)
  • V. Deretic et al.

    Autophagy balances inflammation in innate immunity

    Autophagy

    (2018)
  • S.S. Singh et al.

    Dual role of autophagy in hallmarks of cancer

    Oncogene

    (2018)
  • E. Latz et al.

    Activation and regulation of the inflammasomes, Nature reviews

    Immunology

    (2013)
  • J.A. Duncan et al.

    The NLRC4 inflammasome

    Immunol. Rev.

    (2018)
  • J. Lugrin et al.

    The AIM2 inflammasome: sensor of pathogens and cellular perturbations

    Immunol. Rev.

    (2018)
  • O. Schnappauf et al.

    The pyrin inflammasome in health and disease

    Front. Immunol.

    (2019)
  • S. Taniguchi et al.

    Regulatory molecules involved in inflammasome formation with special reference to a key mediator protein

    ASC Semin. Immunopathol.

    (2007)
  • G. Sollberger et al.

    Caspase-1: the inflammasome and beyond

    Innate Immun.

    (2014)
  • J. Shi et al.

    Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death

    Nature

    (2015)
  • W.T. He et al.

    Gasdermin D is an executor of pyroptosis and required for interleukin-1beta secretion

    Cell Res.

    (2015)
  • J. Tschopp et al.

    NLRP3 inflammasome activation: the convergence of multiple signalling pathways on ROS production?

    Nat. Rev. Immunol.

    (2010)
  • T. Liu et al.

    NF-κB signaling in inflammation

    Signal Transduct. Target. Ther.

    (2017)
  • Cited by (0)

    View full text