Background:The tumor suppressor gene HIC1 (hypermethylated in cancer 1) encodes a transcriptional repressor SUMOylated at Lys-314. Results: DNA damage favors SUMOylation of HIC1 and its interaction with MTA1 to regulate the DNA repair process. Conclusion: Our results demonstrate that HIC1 is implicated in the DNA damage response. Significance: Our work could help explain a mechanism whereby HIC1 loss contributes to tumorigenesis.

Posttranslational modifications (PTMs) of transcription regulatory proteins allow the integration of various signaling and environmental cues into highly dynamic and controlled responses, thereby achieving coordinated gene expression programs essential for cell proliferation or differentiation.The transcription factor BCL11B/CTIP2 was independently isolated as an interacting partner of chicken ovalbumin upstream promoter transcription factor (COUP-TF) in neurons and as a tumor suppressor gene in mouse models of gamma ray-induced thymic lymphomas (1-3). Besides its expression in the central nervous system (CNS), BCL11B was shown to be widely expressed in all T-cell subsets, starting from the double-negative stage 2 (DN2 stage) and to be involved in various aspects of development, function, and survival of T cells (4). Indeed, BCL11B is a focal point essential for several checkpoints involved in T-cell commitment in early progenitors, selection at the DN2 stage, and differentiation of peripheral T cells (5-9). Furthermore, monoallelic BCL11B deletions or missense mutations have been identified in the major molecular subtypes of T-cell acute lymphoblastic leukemia (10). Therefore, these observations together with the occurrence of deletions and mutations in gamma ray-induced thymomas in mice identify BCL11B as a haploinsufficient tumor suppressor gene (11).BCL11B is essential for T-cell development and is considered a "guardian of T cell fate" (12). Its closely related paralog BCL11A is essential for normal lymphopoiesis and hemoglobin switching during erythroid differentiation (13-15). Thus, these two transcription factors appear to be key regulators of fundamental differentiation programs during normal hematopoiesis.BCL11B represses transcription of its target genes through interaction with several chromatin remodelling complexes and notably recruits NuRD complexes (nuclear remodeling and deacetylation complexes) via interaction with MTA1 and MTA2 (4,11,[16][17][18]. Although originally characterized as a sequence-specific transcriptional repressor, BCL11B also behaves as a context-dependent transcriptional activator of the IL-2 and Cot kinase genes in CD4 ϩ T-cell activation (19, 20). This dual behavior of BCL11B as a transcriptional repressor and activator is not fully understood but clearly relies on a dynamic cross talk between BCL11B PTMs. Indeed, mass spectrometry analyses of thymocytes isolated from 4-to 8-week-old mice and stimulated with a mixture of phorbol ester and calcium ionophore used as an in vitro model mimicking T-cell receptor (TCR) activation identified several mitogen-activated protein kinase (MAPK) phosphorylation sites of BCL11B and confirmed its

Background:The transcriptional repressor HIC1 is a tumor suppressor gene epigenetically silenced in many human tumors. Results: We identified ␤-2 adrenergic receptor (ADRB2) as a new direct target gene of HIC1. Conclusion: Early inactivation of HIC1 in breast carcinomas could predispose to stress-induced metastasis through up-regulation of the ␤-2 adrenergic receptor. Significance: Characterization of HIC1 target genes may explain how its inactivation contributes to tumorigenesis.

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Polycomb repressive complex 2 (PRC2) allows the deposition of H3K27me3. PRC2 facultative subunits modulate its activity and recruitment such as hPCL3/ PHF19, a human ortholog of Drosophila Polycomb-like protein (PCL). These proteins contain a TUDOR domain binding H3K36me3, two PHD domains and a "Winged-helix" domain involved in GC-rich DNA binding. The human PCL3 locus encodes the fulllength hPCL3L protein and a shorter isoform, hPCL3S containing the TUDOR and PHD1 domains only. In this study, we demonstrated by RT-qPCR analyses of 25 prostate tumors that hPCL3S is frequently up-regulated. In addition, hPCL3S is overexpressed in the androgen-independent DU145 and PC3 cells, but not in the androgen-dependent LNCaP cells. hPCL3S knockdown decreased the proliferation and migration of DU145 and PC3 whereas its forced expression into LNCaP increased these properties. A mutant hPCL3S unable to bind H3K36me3 (TUDOR-W50A) increased proliferation and migration of LNCaP similarly to wt hPCL3S whereas inactivation of its PHD1 domain decreased proliferation. These effects partially relied on the up-regulation of genes known to be important for the proliferation and/or migration of prostate cancer cells such as S100A16, PlexinA2, and Spondin1. Collectively, our results suggest hPCL3S as a new potential therapeutic target in castration resistant prostate cancers.

While it is now accepted that nutrition can influence the epigenetic modifications occurring in colorectal cancer (CRC), the underlying mechanisms are not fully understood. Among the tumor suppressor genes frequently epigenetically downregulated in CRC, the four related genes of the UNC5 family: UNC5A, UNC5B, UNC5C and UNC5D encode dependence receptors that regulate the apoptosis/survival balance. Herein, in a mouse model of CRC, we found that the expression of UNC5A, UNC5B and UNC5C was diminished in tumors but only in mice subjected to a High Carbohydrate Diet (HCD) thus linking nutrition to their repression in CRC. O-GlcNAcylation is a nutritional sensor which has enhanced levels in CRC and regulates many cellular processes amongst epigenetics. We then investigated the putative involvement of O-GlcNAcylation in the epigenetic downregulation of the UNC5 family members. By a combination of pharmacological inhibition and RNA interference approaches coupled to RT-qPCR (Reverse Transcription-quantitative Polymerase Chain Reaction) analyses, promoter luciferase assay and CUT&RUN (Cleavage Under Target & Release Using Nuclease) experiments, we demonstrated that the O-GlcNAcylated form of the histone methyl transferase EZH2 (Enhancer of Zeste Homolog 2) represses the transcription of UNC5A in human colon cancer cells. Collectively, our data support the hypothesis that O-GlcNAcylation could represent one link between nutrition and epigenetic downregulation of key tumor suppressor genes governing colon carcinogenesis including UNC5A.