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A growing number of studies suggest a tumor suppressor role for the SWI/SNF complex involved in the remodeling of chromatin. Alterations of this complex have been found in many tumors of different origins, with topographic, morphologic and phenotypic diversity. Notably, they define 2 types of thoracic tumors: SMARCA4-deficient non-small cell lung carcinoma and SMARCA4-deficient sarcoma. Some clinical features appear to be common to both, such as intrathoracic localization, smoking exposure, male predominance and poor prognosis. However, the histological distinction between these two entities is sometimes difficult and it is not excluded that these entities belong to the same tumor spectrum with different degrees of differentiation. The therapy of these tumors is not yet codified. These tumors do not seem associated with oncogenic driver mutations allowing the prescription of targeted therapy, but immunotherapy has been shown to be effective in rare reported cases. More specific treatments using EZH2 inhibitors also seem promising in SMARCA4 deficient sarcomas.

International audience; Epigenetic regulation is altered in many diseases, in particular in cancer. Several molecules acting on the epigenetic regulation are in clinical trials, some of which are already approved for the treatment of haematological cancers. We will summarize here the latest advances in the discovery of chemical molecules acting on DNA and histone methylation. These new molecules bring new promises but also limitations that we will discuss.; La régulation épigénétique est altérée dans de nombreuses maladies, dont le cancer. Plusieurs molécules agissant sur la régulation épigénétique sont testées en phase clinique ou déjà approuvées pour le traitement de leucémies, par exemple. Nous allons ici résumer les dernières avancées concernant la découverte de molécules chimiques agissant sur la méthylation de l'ADN et des histones. Ces molécules apportent de nouvelles promesses mais ont aussi des limites que nous allons discuter.

Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase that functions as the catalytic subunit of the polycomb repressive complex 2 (PRC2). PRC2 represses gene transcription through tri-methylation of lysine 27 of histone 3 (H3K27me3) by its catalytic subunit EZH2. EZH2 is also involved in normal B cell differentiation. EZH2 deregulation has been described in many cancer types including hematological malignancies. The oncogenic addiction of tumor cells to EZH2 represents a therapeutic target in several hematological malignancies and solid cancers. Specific small molecules have been recently developed to target cancer cells with EZH2 overexpression or activating mutation. Their therapeutic potential is currently under evaluation. In particular, EZH2 is overexpressed in multiple myeloma (MM), a neoplasia characterized by the accumulation of clonal plasma cells within the bone marrow, with biological functions in the pathophysiology. This review summarizes the roles of EZH2 in B cell differentiation and pathologic hematological processes with a particular focus in multiple myeloma. We also discuss recent advances in the development of EZH2 inhibitors for the personalized treatment of patients with hematological malignancies.

Polycomb Group proteins (PcG) are repressive epigenetic factors essential for development and involved in numerous cancer processes, yet their modes of action and recruitment to specific genomic loci are not fully understood. Recently, it has been shown that the PcG protein recruitment is a dynamic process, contrary to what was foreseen in the initial hierarchical model. In addition, EZH2, a key PcG protein, can be associated to transcribed genes, challenging the former function of PcG proteins as transcriptional repressors. Furthermore, the dual role of EZH2, which can act as an oncogene or a tumor suppressor depending on the cellular type, illustrates the functional complexity of PcG proteins.

A meta-analysis of recent data from the literature underscores the considerable body of present knowledge concerning prostate carcinogenesis, in part due to the numerous molecular biology tools now at our disposal. As concerns early events, much interest is being paid to modifications in the expression of GSTP1 and NKX3.1 occurring in totipotent stem cell populations. The discovery of fusion genes implicating TMPRSS2 and ERG (and, on rare occasions, other ETS family transcription factors) constitutes a major advance. Under physiological androgenic stimulation, the presence of these fusion genes leads to overexpression of genes involved in cell growth and differentiation. Concomitantly, alterations in numerous signalling pathways (growth factors, Wnt-beta catenine, PI3K/Akt) are responsible for the onset of an aggressive tumor phenotype. Hormono-independence is currently explained by an amplification of, or mutations in, androgenic receptors. These are facilitated by genomic instabilities linked to alterations in proteins which regulate gene expression, such as EZH2, and by the influence of the tumor microenvironment. Disturbances in the interactions between tumor cells and the microenvironment contribute to local extension of the tumor. Changes in the expression of E-cadherin are responsible for modifications in cell adhesion to the extracellular matrix. The expression of metalloproteases and of angiogenic factors favors tumor dissemination. Finally, the bone tropism in prostate metastases is probably linked to osteomimetic properties of prostate tumor cells which are capable of expressing certain proteins involved in bone remodelling, such as Runx-2, BSP (bone sialoprotein) and BMP (bone morphogenetic protein). Numerous studies remain to be carried out in order to correlate the identified genetic profiles and molecular anomalies with tumor prognosis. Nevertheless, the possibility of decrypting these anomalies for use in therapeutic applications is encouraging.