Inflammation is an intricate immune response against infection and tissue damage. While the initial immune response is important for preventing tumorigenesis, chronic inflammation is implicated in cancer pathogenesis. It has been linked to various stages of tumor development including transformation, proliferation, angiogenesis, and metastasis. Immune cells, through the production of inflammatory mediators such as cytokines, chemokines, transforming growth factors, and adhesion molecules contribute to the survival, growth, and progression of the tumor in its microenvironment. The aberrant expression and secretion of pro-inflammatory and growth factors by the tumor cells result in the recruitment of immune cells, thus creating a mutual crosstalk. The reciprocal signaling between the tumor cells and the immune cells creates and maintains a successful tumor niche. Many inflammatory factors are regulated by epigenetic mechanisms including DNA methylation and histone modifications. In particular, DNA and histone methylation are crucial forms of transcriptional regulation and aberrant methylation has been associated with deregulated gene expression in oncogenesis. Such deregulations have been reported in both solid tumors and hematological malignancies. With technological advancements to study genome-wide epigenetic landscapes, it is now possible to identify molecular mechanisms underlying altered inflammatory profiles in cancer. In this review, we discuss the role of DNA and histone methylation in regulation of inflammatory pathways in human cancers and review the merits and challenges of targeting inflammatory mediators as well as epigenetic regulators in cancer.

No abstract

The relatively quiet mutational landscape of rhabdomyosarcoma (RMS) suggests that epigenetic deregulation could be central to oncogenesis and tumour aggressiveness. Histone variants have long been recognised as important epigenetic regulators of gene expression. However, the role of histone variants in RMS has not been studied hitherto. In this study, we show that histone variant H3.3 is overexpressed in alveolar RMS (ARMS), an aggressive subtype of RMS. Functionally, knockdown of H3F3A, which encodes for H3.3, significantly impairs the ability of ARMS cells to undertake migration and invasion and reduces Rho activation. In addition, a striking reduction in metastatic tumour burden and improved survival is apparent in vivo. Using RNA-sequencing and ChIP-sequencing analyses, we identified melanoma cell adhesion molecule (MCAM/CD146) as a direct downstream target of H3.3. Loss of H3.3 resulted in a reduction in the presence of active marks and an increase in the occupancy of H1 at the MCAM promoter. Cell migration and invasion were rescued in H3F3A-depleted cells through MCAM overexpression. Moreover, we identified G9a, a lysine methyltransferase encoded by EHMT2, as an upstream regulator of H3F3A. Therefore, this study identifies a novel H3.3 dependent axis involved in ARMS metastasis. These findings establish the potential of MCAM as a therapeutic target for high-risk ARMS patients.

No abstract