Regulation and function of O-GlcNAcylation in TAM macrophage differentiation and tumor progression

• Grant number: 17/20692-5
• Support type: Scholarships in Brazil - Doctorate
• Effective date (Start): January 01, 2018
• Effective date (End): June 30, 2020
• Field of knowledge: Biological Sciences - Immunology
• Principal Investigator: José Carlos Farias Alves Filho
• Grantee: João Paulo Mesquita Luiz
• Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases, AP.CEPID

Abstract

Macrophage are essential components of innate immunity that contributes for the tissue homeostasis maintenance, host defense against infections and participates in tumor promotion. Macrophage plasticity is notable feature that allows responding to a different of environmental signals by changing their phenotype toward to pro-inflammatory (M1) or anti-inflammatory (M2). In many types of cancer tumor-associated macrophages, which exhibits an immunosuppressive profile, are involved in tumor growth, metastasis, immune evasion and resistance to chemotherapy. Therefore, the identification of key target molecules for regulation of TAM macrophage differentiation is an important step for development of new therapeutic strategies against several types of cancer. Recent studies have identified a tight regulation of the immune system by cell metabolism. O-GlcNAc transferase (OGT) is an enzyme responsible for the addition UDP-GlcNAc (O-GlcNAcylation), the final product of the Hexosamine Biosynthetic Pathway (HBP), in a number of different intracellular proteins, regulating several fundamental biological activities, including cell activation, differentiation and proliferation. OGT is a known epigenetic regulator capable of controlling the expression and estability of a number of transcription factors, including c-Myc. In turn, c-Myc plays an important role in the regulation of the alternative activation of M2 macrophages. Despite this, there are few studies about overall effects of OGT-mediated O-GlcNAcylation on immunologic function of macrophage and its clinical relevance remains unclear. Our initial results, using conditional OGT knockout mice in myeloid cells, demonstrate that OGT is crucial for the M2 macrophage polarization, while it is able to inhibit polarization of M1 macrophages. Thus, the hypothesis of this work is that OGT-mediated O-GlcNAacylation regulates c-Myc stability, modulating TAM macrophage differentiation and consequently the susceptibility to tumor development. Therefore, the present project will investigate the involvement of OGT in macrophage during the immune regulation process and tumor progression, which will allow the identification new therapeutic targets against the cancer. (AU)