DNA methylation of tumor suppressor genes is a frequent mechanism of transcriptional silencing in cancer. The molecular mechanisms underlying the specificity of methylation are unknown. We report here that the leukemia-promoting PML-RAR fusion protein induces gene hypermethylation and silencing by recruiting DNA methyltransferases to target promoters and that hypermethylation contributes to its leukemogenic potential. Retinoic acid treatment induces promoter demethylation, gene reexpression, and reversion of the transformed phenotype. These results establish a mechanistic link between genetic and epigenetic changes during transformation and suggest that hypermethylation contributes to the early steps of carcinogenesis.

Epigenetic modifications regulate developmental genes involved in stem cell identity and lineage choice. NFI-A is a posttranscriptional microRNA-223 (miR-223) target directing human hematopoietic progenitor lineage decision: NFI-A induction or silencing boosts erythropoiesis or granulopoiesis, respectively. Here we show that NFI-A promoter silencing, which allows granulopoiesis, is guaranteed by epigenetic events, including the resolution of opposing chromatin “bivalent domains,” hypermethylation, recruitment of polycomb (PcG)–RNAi complexes, and miR-223 promoter targeting activity. During granulopoiesis, miR-223 localizes inside the nucleus and targets the NFI-A promoter region containing PcGs binding sites and miR-223 complementary DNA sequences, evolutionarily conserved in mammalians. Remarkably, both the integrity of the PcGs-RNAi complex and DNA sequences matching the seed region of miR-223 are required to induce NFI-A transcriptional silencing. Moreover, ectopic miR-223 expression in human myeloid progenitors causes heterochromatic repression of NFI-A gene and channels granulopoiesis, whereas its stable knockdown produces the opposite effects. Our findings indicate that, besides the regulation of translation of mRNA targets, endogenous miRs can affect gene expression at the transcriptional level, functioning in a critical interface between chromatin remodeling complexes and the genome to direct fate lineage determination of hematopoietic progenitors.

P53 mutations have profound effects on non-small-cell lung cancer (NSCLC) resistance to chemotherapeutic treatments. Mutant p53 proteins are usually expressed at high levels in tumors, where they exert oncogenic functions. Here we show that p53R175H, a hotspot p53 mutant, induces microRNA (miRNA)-128-2 expression. Mutant p53 binds to the putative promoter of miR128-2 host gene, ARPP21, determining a concomitant induction of ARPP21 mRNA and miR-128-2. miR-128-2 expression in lung cancer cells inhibits apoptosis and confers increased resistance to cisplatin, doxorubicin and 5-fluorouracyl treatments. At the molecular level, miR-128-2 post-transcriptionally targets E2F5 and leads to the abrogation of its repressive activity on p21^waf1 transcription. p21^waf1 protein localizes to the cytoplasmic compartment, where it exerts an anti-apoptotic effect by preventing pro-caspase-3 cleavage. This study emphasizes miRNA-128-2 role as a master regulator in NSCLC chemoresistance.

The epidermal growth factor receptor (EGFR) is a protein embedded in the outer membrane of epithelial and mesenchymal cells, bone cells, blood and immune cells, heart cells, glia and stem neural cells. It belongs to the ErbB family, which includes three other related proteins: HER2/ErbB2/c-neu, HER3/ErbB3, and HER4/ErbB4. EGFR binds to seven known signaling molecules, including epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-α). This binding triggers the formation of receptor pairs (dimers), self-phosphorylation of EGFR, and the activation of several signaling pathways within the cell. These pathways influence various cellular processes like proliferation, differentiation, migration, and survival. EGFR plays a critical role in both development and tissue homeostasis, including tissue repair and adult organ regeneration. Altered expression of EGFR is linked to disruption of tissue homeostasis and various diseases, among which cancer. This review focuses on how EGFR contributes to the development of different organs like the placenta, gut, liver, bone, skin, brain, T cell regulation, pancreas, kidneys, mammary glands and lungs along with their associated pathologies. The involvement of EGFR in organ-specific branching morphogenesis process is also discussed. The level of EGFR activity and its impact vary across different organs. Factors as the affinity of its ligands, recycling or degradation processes, and transactivation by other proteins or environmental factors (such as heat stress and smoking) play a role in regulating EGFR activity. Understanding EGFR’s role and regulatory mechanisms holds promise for developing targeted therapeutic strategies.