Transcription factor forkhead box protein P2 (FOXP2) plays an essential role in the development of language and speech. However, the transcriptional activity of FOXP2 regulated by the post-translational modifications remains unknown. Here we demonstrated that FOXP2 is clearly defined as a SUMO target protein at the cellular levels as FOXP2 is covalently modified by both SUMO1 and SUMO3. Furthermore, SUMOylation of FOXP2 was significantly decreased by SENP2 (a specific SUMOylation protease). We further showed that FOXP2 is selectively SUMOylated in vivo on a phylogenetically conserved lysine 674 but the SUMOylation does not alter subcellular localization and stability of FOXP2. Interestingly, we observed that human etiological FOXP2 R553H mutation robustly reduces its SUMOylation potential as compared to wild-type FOXP2. In addition, the acidic residues downstream the core SUMO motif on FOXP2 are required for its full SUMOylation capacity. Finally, our functional analysis using reporter gene assays showed that SUMOylation may modulate transcriptional activity of FOXP2 in regulating downstream target genes (DISC1, SRPX2 and MiR200c). Altogether, we provide the first evidence that FOXP2 is a substrate for SUMOylation and SUMOylation of FOXP2 plays a functional role in regulating its transcriptional activity.
Transcription factor Forkhead Box Protein M1 (FOXM1) is a well-known master regulator in controlling cell-cycle pathways essential for DNA replication and mitosis, as well as cell proliferation. Among the three major isoforms of FOXM1, FOXM1B is highly associated with tumor growth and metastasis. The activities of FOXM1B are modulated by post-translational modifications (PTMs), such as phosphorylation, but whether it is modified by small ubiquitin-related modifier (SUMO) remains unknown. The aim of the current study was to determine whether FOXM1B is post-translationally modified by SUMO proteins and also to identify SUMOylation of FOXM1B on its target gene transcription activity. Here we report that FOXM1B is clearly defined as a SUMO target protein at the cellular levels. Moreover, a SUMOylation protease, SENP2, significantly decreased SUMOylation of FOXM1B. Notably, FOXM1B is selectively SUMOylated at lysine residue 463. While SUMOylation of FOXM1B is required for full repression of its target genes MiR-200b/c and p21, SUMOylation of FOXM1B is essential for full activation of JNK1 gene. Overall, we provide evidence that FOXM1B is post-translationally modified by SUMO and SUMOylation of FOXM1B plays a functional role in regulation of its target gene activities.
BackgroundPrevious data have reported that the growth of established tumors may be facilitated by postsepsis disorder through changes in the microenvironment and immune dysfunction. However, the influence of postsepsis disorder in initial carcinogenesis remains elusive.MethodsIn the present work, the effect of postsepsis on inflammation-induced early carcinogenesis was evaluated in an experimental model of colitis-associated colorectal cancer (CAC). We also analyzed the frequency and role of intestinal T regulatory cells (Treg) in CAC carcinogenesis.ResultsThe colitis grade and the tumor development rate were evaluated postmortem or in vivo through serial colonoscopies. Sepsis-surviving mice (SSM) presented with a lower colonic DNA damage, polyp incidence, reduced tumor load, and milder colitis than their sham-operated counterparts. Ablating Treg led to restoration of the ability to develop colitis and tumor polyps in the SSM, in a similar fashion to that in the sham-operated mice. On the other hand, the growth of subcutaneously inoculated MC38luc colorectal cancer cells or previously established chemical CAC tumors was increased in SSM.ConclusionOur results provide evidence that postsepsis disorder has a dual effect in cancer development, inhibiting inflammation-induced early carcinogenesis in a Treg-dependent manner, while increasing the growth of previously established tumors.
Introduction: Inflammation influences colorectal carcinogenesis and patients with inflammatory bowel disease are more prone to develop colorectal cancer (CRC). Varipous evidence points towards sepsis-surviving individuals experiencing a prolonged state of immunosuppression. The aim of this study was to evaluate if colitis-induced CRC initiation and progression was affected in sepsis-surviving mice. Experimental Procedures: C57Bl6 mice were submitted to cecal ligation and puncture (CLP) model, and after 15 days, sepsis-surviving mice and one control group received azoxymethane (AOM, 10 mg/kg, ip) and dextran sodium sulfate (DSS 2%, ad libitum, 3 cycles of 5 days) on days 20-25, 40-45, and 60-65 post-CLP. Colitis and tumor development were evaluated by serial colonoscopies. Cytokines (IFN-γ, IL-1β, TNF, IL-6, IL-17, TGF), chemokines (KC and MIG), and GM-CSF were quantified on days 0, 12, 52, and 65 by Milliplex and Treg cells on days 12 and 65 by flow cytometry. Two groups of C57 animals received cyclophosphamide (CYP) (100 mg/kg, ip), and two groups of animals expressing diphtheria toxin (DTX) receptor under-regulation of Foxp3 received DTX (0.5 mg/animal, ip) before the AOM/DSS protocol. Another animal cohort was submitted to CLP after receiving AOM/DSS, and two other groups were injected with murine CRC cells (MC38luc) 105 cells s.c. or 106 cells intra-splenically 15 days post-CLP. Results: Sepsis-surviving animals showed reduced colitis and lower incidence, number of tumors, and tumor load than control animals. Lower levels of IFN-γ in the colon on day 12, and of IL-1β, TNF, IL-6, IL-17, KC, and MIG on days 12 and 65, in addition to IL-33, TG,F and GM-CSF on day 65, were detected in sepsis-surviving mice. Tregs accumulated in a more pronounced fashion in sepsis-surviving mice on D15. Treg depletion through CYP or DTX restored colitis and CRC incidence in post-sepsis mice. Conversely, mice submitted to sepsis after AOM/DSS showed an increase in tumor load 30 days after CLP when compared to controls. Furthermore, in the subcutaneous and intrasplenic colorectal cancer model, increased tumor growth was observed in post-sepsis animals when compared to the controls. Conclusion: Colitis-dependent CRC carcinogenesis was reduced by post-sepsis state in mice in a Treg-dependent manner. Citation Format: Caio Abner Vitorino Goncalves Leite, Jose Mauricio Segundo Correia Mota, Kalil Alves Lima, Leticia Almeida Nascimento, Marcela Davoli Ferreira, Paula Ramos Viacava, Maria Dirlei Begnami, Jose Carlos Alves Filho, Roberto Cesar Pereira Lima Jr., Vladmir Claudio Cordeiro Lima, Fernando Queiroz Cunha. Colorectal carcinogenesis is precluded by intestinal Treg cell accumulation in post-sepsis state [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr A70.
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