ncRNAs Orchestrate Chemosensitivity Induction by Neddylation Blockades.

We performed an integrative transcriptomic in silico analysis using lung adenocarcinoma A549 cells treated with the neddylation inhibitor MLN4924 and the gefitinib-resistant PC9 cell line (PC9GR). We focused on the transcriptional effects of the top differentially expressed ncRNA biotypes and their correlating stemness factors. Interestingly, MLN4924-treated cells showed a significant upregulation of mRNAs involved in carcinogenesis, cell attachment, and differentiation pathways, as well as a parallel downregulation of stemness maintenance and survival signaling pathways, an effect that was inversely observed in PC9GR cells. Moreover, we found that stemness factor expression could be contrasted by selected up-regulated ncRNAs upon MLN4924 treatment in a dose and time-independent manner. Furthermore, upregulated miRNAs and lncRNA-targeted mRNAs showed an evident enrichment of proliferation, differentiation, and apoptosis pathways, while downregulated ncRNA-targeted mRNAs were implicated in stem cell maintenance. Finally, our results proved that stemness (KLF4 and FGFR2) and epithelial-mesenchymal transition (ZEB2, TWIST2, SNAI2, CDH2, and VIM) factors, which are highly expressed in PC9GR cells compared to gefitinib-sensitive PC9 cells, could be abrogated with the neddylation inhibitor MLN4924 mainly through activation of epithelial differentiation pathways, thus exerting a protective role in lung cancer cells and chemosensitivity against lung tumorigenic transformation.

Cancer cell plasticity during tumor progression, metastasis and response to therapy.

Cell plasticity represents the ability of cells to be reprogrammed and to change their fate and identity, enabling homeostasis restoration and tissue regeneration following damage. Cell plasticity also contributes to pathological conditions, such as cancer, enabling cells to acquire new phenotypic and functional features by transiting across distinct cell states that contribute to tumor initiation, progression, metastasis and resistance to therapy. Here, we review the intrinsic and extrinsic mechanisms driving cell plasticity that promote tumor growth and proliferation as well as metastasis and drug tolerance. Finally, we discuss how cell plasticity could be exploited for anti-cancer therapy.

EP300 as a Molecular Integrator of Fibrotic Transcriptional Programs.

Fibrosis is a condition characterized by the excessive accumulation of extracellular matrix proteins in tissues, leading to organ dysfunction and failure. Recent studies have identified EP300, a histone acetyltransferase, as a crucial regulator of the epigenetic changes that contribute to fibrosis. In fact, EP300-mediated acetylation of histones alters global chromatin structure and gene expression, promoting the development and progression of fibrosis. Here, we review the role of EP300-mediated epigenetic regulation in multi-organ fibrosis and its potential as a therapeutic target. We discuss the preclinical evidence that suggests that EP300 inhibition can attenuate fibrosis-related molecular processes, including extracellular matrix deposition, inflammation, and epithelial-to-mesenchymal transition. We also highlight the contributions of small molecule inhibitors and gene therapy approaches targeting EP300 as novel therapies against fibrosis.

ERK activation modulates invasiveness and Reactive Oxygen Species (ROS) production in triple negative breast cancer cell lines.

Triple negative breast cancer (TNBC) is the breast cancer subtype with the worst prognosis and still lacks a targeted therapy. In this study, we found increased ERK phosphorylation in TNBC cell lines and an important role for ERK in sustaining the migration of TNBC cells. Although ROS have been suggested to have an important role in sustaining MAPK signaling, antioxidant treatment increased ERK phosphorylation, probably suggesting increased invasive potential. Interestingly, treatment with PD0325901 (PD), a MEK inhibitor, decreased ROS levels in TNBC cells and decreased mitochondrial fragmentation in the MDAMB231 cell line. Our data supports an important role for MEK/ERK in TNBC, sustaining cellular migration, regulating mitochondrial dynamics and ROS production in this breast cancer subtype.

Epigenetic Regulation in Exposome-Induced Tumorigenesis: Emerging Roles of ncRNAs.

Environmental factors, including pollutants and lifestyle, constitute a significant role in severe, chronic pathologies with an essential societal, economic burden. The measurement of all environmental exposures and assessing their correlation with effects on individual health is defined as the exposome, which interacts with our unique characteristics such as genetics, physiology, and epigenetics. Epigenetics investigates modifications in the expression of genes that do not depend on the underlying DNA sequence. Some studies have confirmed that environmental factors may promote disease in individuals or subsequent progeny through epigenetic alterations. Variations in the epigenetic machinery cause a spectrum of different disorders since these mechanisms are more sensitive to the environment than the genome, due to the inherent reversible nature of the epigenetic landscape. Several epigenetic mechanisms, including modifications in DNA (e.g., methylation), histones, and noncoding RNAs can change genome expression under the exogenous influence. Notably, the role of long noncoding RNAs in epigenetic processes has not been well explored in the context of exposome-induced tumorigenesis. In the present review, our scope is to provide relevant evidence indicating that epigenetic alterations mediate those detrimental effects caused by exposure to environmental toxicants, focusing mainly on a multi-step regulation by diverse noncoding RNAs subtypes.

Reactive oxygen species: Role in carcinogenesis, cancer cell signaling and tumor progression.

Cancer is one of the major causes of death in the world and its global burden is expected to continue increasing. In several types of cancers, reactive oxygen species (ROS) have been extensively linked to carcinogenesis and cancer progression. However, studies have reported conflicting evidence regarding the role of ROS in cancer, mostly dependent on the cancer type or the step of the tumorigenic process. We review recent studies describing diverse aspects of the interplay of ROS with cancer in the different stages of cancer progression, with a special focus on their role in carcinogenesis, their importance for cancer cell signaling and their relationship to the most prevalent cancer risk factors.