Hyaluronic acid (HA) has been shown to promote angiogenesis. However, the mechanism behind this effect remains largely unknown. Therefore, in this study, the mechanism of HA-induced angiogenesis was examined. CD44 and PKCδ were shown to be necessary for induction of the receptor for HA-mediated cell motility (RHAMM), a HA-binding protein. RHAMM was necessary for HA-promoted cellular invasion and endothelial cell tube formation. Cytokine arrays showed that HA induced the expression of plasminogen activator-inhibitor-1 (PAI), a downstream target of TGFβ receptor signaling. The induction of PAI-1 was dependent on CD44 and PKCδ. HA also induced an interaction between RHAMM and TGFβ receptor I, and induction of PAI-1 was dependent on RHAMM and TGFβ receptor I. Histone deacetylase 3 (HDAC3), which is decreased by HA via rac1, reduced induction of plasminogen activator inhibitor-1 (PAI-1) by HA. ERK, which interacts with RHAMM, was necessary for induction of PAI-1 by HA. Snail, a downstream target of TGFβ signaling, was also necessary for induction of PAI-1. The down regulation of PAI-1 prevented HA from enhancing endothelial cell tube formation and from inducing expression of angiogenic factors, such as ICAM-1, VCAM-1 and MMP-2. HDAC3 also exerted reduced expression of MMP-2. In this study, we provide a novel mechanism of HA-promoted angiogenesis, which involved RHAMM-TGFβRI signaling necessary for induction of PAI-1.

The role of the cancer/testis antigen CAGE in drug resistance was investigated. The drug-resistant human melanoma Malme3M (Malme3M^R) and the human hepatic cancer cell line SNU387 (SNU387^R) showed in vivo drug resistance and CAGE induction. Induction of CAGE resulted from decreased expression and thereby displacement of DNA methyltransferase 1(DNMT1) from CAGE promoter sequences. Various drugs induce expression of CAGE by decreasing expression of DNMT1, and hypomethylation of CAGE was correlated with the increased expression of CAGE. Down-regulation of CAGE in these cell lines decreased invasion and enhanced drug sensitivity resulting from increased apoptosis. Down-regulation of CAGE also led to decreased anchorage-independent growth. Down-regulation of CAGE led to increased expression of p53, suggesting that CAGE may act as a negative regulator of p53. Down-regulation of p53 enhanced resistance to drugs and prevented drugs from exerting apoptotic effects. In SNU387^R cells, CAGE induced the interaction between histone deacetylase 2 (HDAC2) and Snail, which exerted a negative effect on p53 expression. Chromatin immunoprecipitation assay showed that CAGE, through interaction with HDAC2, exerted a negative effect on p53 expression in Malme3M^R cells. These results suggest that CAGE confers drug resistance by regulating expression of p53 through HDAC2. Taken together, these results show the potential value of CAGE as a target for the development of cancer therapeutics.

Epidermal growth factor receptor (EGFR) plays critical roles in cell proliferation, tumorigenesis, and anti-cancer drug resistance. Overexpression and somatic mutations of EGFR result in enhanced cancer cell survival. Therefore, EGFR can be a target for the development of anti-cancer therapy. Patients with cancers, including non-small cell lung cancers (NSCLC), have been shown to response to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) and anti-EGFR antibodies. However, resistance to these anti-EGFR treatments has developed. Autophagy has emerged as a potential mechanism involved in the acquired resistance to anti-EGFR treatments. Anti-EGFR treatments can induce autophagy and result in resistance to anti-EGFR treatments. Autophagy is a programmed catabolic process stimulated by various stimuli. It promotes cellular survival under these stress conditions. Under normal conditions, EGFR-activated phosphoinositide 3-kinase (PI3K)/AKT serine/threonine kinase (AKT)/mammalian target of rapamycin (mTOR) signaling inhibits autophagy while EGFR/rat sarcoma viral oncogene homolog (RAS)/mitogen-activated protein kinase kinase (MEK)/mitogen-activated protein kinase (MAPK) signaling promotes autophagy. Thus, targeting autophagy may overcome resistance to anti-EGFR treatments. Inhibitors targeting autophagy and EGFR signaling have been under development. In this review, we discuss crosstalk between EGFR signaling and autophagy. We also assess whether autophagy inhibition, along with anti-EGFR treatments, might represent a promising approach to overcome resistance to anti-EGFR treatments in various cancers. In addition, we discuss new developments concerning anti-autophagy therapeutics for overcoming resistance to anti-EGFR treatments in various cancers.

We have shown the induction of histone deacetylase 3 (HDAC3) in antigen-stimulated rat basophilic leukemia cells via NF-κB. We investigated the role of HDAC3 in allergic skin inflammation. We used a BALB/c mouse model of triphasic cutaneous anaphylaxis (triphasic cutaneous reaction; TpCR) and passive cutaneous anaphylaxis (PCA) to examine the role of HDAC3 in allergic skin inflammation. Triphasic cutaneous reaction involved induction of HDAC3 and was mediated by HDAC3. HDAC3 showed an interaction with FcϵRIβ. Trichostatin A (TSA), an inhibitor of HDAC(s), disrupted this interaction. Cytokine array analysis showed that the down-regulation of HDAC3 led to the decreased secretion of monocyte chemoattractant protein 1 (MCP1). FcϵRI was necessary for induction of HDAC3 and MCP1. ChIP assays showed that HDAC3, in association with Sp1 and c-Jun, was responsible for induction of MCP1 expression. TSA exerted a negative effect on induction of MCP1. HDAC3 exerted a negative regulation on expression of HDAC2 via interaction with Rac1. The down-regulation of HDAC3 or inactivation of Rac1 induced binding of HDAC2 to MCP1 promoter sequences. TSA exerted a negative effect on HDAC3-mediated TpCR. The BALB/c mouse model of PCA involved induction of HDAC3 and MCP1. HDAC3 and MCP1 were necessary for PCA that involved ear swelling, enhanced vascular permeability, and angiogenesis. Recombinant MCP1 enhanced β-hexosaminidase activity and histamine release and also showed angiogenic potential. TSA exerted a negative effect on PCA. Our data show HDAC3 as a valuable target for the development of allergic skin inflammation therapeutics.

Tumor microenvironment consists of cancer cells and various stromal cells such as endothelial cells, cancer-associated fibroblasts (CAFs), myeloid-derived suppressor cells (MDSCs), neutrophils, macrophages, and other innate and adaptive immune cells. Of these innate immune cells, macrophages are an extremely heterogeneous population, and display both pro-inflammatory and anti-inflammatory functions. While M1 macrophages (classically activated macrophages) display anti-tumoral and pro-inflammatory functions, M2 macrophages display pro-tumoral and anti-inflammatory functions. Cellular interactions and molecular factors in the tumor microenvironment affect the polarization of macrophages. We review molecules and immune cells that influence the polarization status of macrophages. Tumor-associated macrophages (TAMs) generally express M2 phenotype, and mediate many processes that include tumor initiation, angiogenesis, and metastasis. A high number of TAMs has been associated with the poor prognosis of cancers. MicroRNAs (miRNAs) have been known to regulate cellular interactions that involve cancer cells and macrophages. Tumor-derived exosomes play critical roles in inducing the M1 or M2-like polarization of macrophages. The roles of exosomal miRNAs from tumor cells in the polarization of macrophages are also discussed and the targets of these miRNAs are presented. We review the effects of exosomal miRNAs from TAMs on cancer cell invasion, growth, and anti-cancer drug resistance. The relevance of exosomal microRNAs (miRNAs) as targets for the development of anti-cancer drugs is discussed. We review recent progress in the development of miRNA therapeutics aimed at elevating or decreasing levels of miRNAs.

Therapies that target oncogenes and immune checkpoint molecules constitute a major group of treatments for metastatic melanoma. A mutation in BRAF (BRAF V600E) affects various signaling pathways, including mitogen activated protein kinase (MAPK) and PI3K/AKT/mammalian target of rapamycin (mTOR) in melanoma. Target-specific agents, such as MAPK inhibitors improve progression-free survival. However, BRAF^V600E mutant melanomas treated with BRAF kinase inhibitors develop resistance. Immune checkpoint molecules, such as programmed death-1 (PD-1) and programmed death ligand-1(PD-L1), induce immune evasion of cancer cells. MAPK inhibitor resistance results from the increased expression of PD-L1. Immune checkpoint inhibitors, such as anti-PD-L1 or anti-PD-1, are main players in immune therapies designed to target metastatic melanoma. However, melanoma patients show low response rate and resistance to these inhibitors develops within 6–8 months of treatment. Epigenetic reprogramming, such as DNA methylaion and histone modification, regulates the expression of genes involved in cellular proliferation, immune checkpoints and the response to anti-cancer drugs. Histone deacetylases (HDACs) remove acetyl groups from histone and non-histone proteins and act as transcriptional repressors. HDACs are often dysregulated in melanomas, and regulate MAPK signaling, cancer progression, and responses to various anti-cancer drugs. HDACs have been shown to regulate the expression of PD-1/PD-L1 and genes involved in immune evasion. These reports make HDACs ideal targets for the development of anti-melanoma therapeutics. We review the mechanisms of resistance to anti-melanoma therapies, including MAPK inhibitors and immune checkpoint inhibitors. We address the effects of HDAC inhibitors on the response to MAPK inhibitors and immune checkpoint inhibitors in melanoma. In addition, we discuss current progress in anti-melanoma therapies involving a combination of HDAC inhibitors, immune checkpoint inhibitors, and MAPK inhibitors.