Insights into the post-translational modification and its emerging role in shaping the tumor microenvironment

Abstract

More and more in-depth studies have revealed that the occurrence and development of tumors depend on gene mutation and tumor heterogeneity. The most important manifestation of tumor heterogeneity is the dynamic change of tumor microenvironment (TME) heterogeneity. This depends not only on the tumor cells themselves in the microenvironment where the infiltrating immune cells and matrix together forming an antitumor and/or pro-tumor network. TME has resulted in novel therapeutic interventions as a place beyond tumor beds. The malignant cancer cells, tumor infiltrate immune cells, angiogenic vascular cells, lymphatic endothelial cells, cancer-associated fibroblastic cells, and the released factors including intracellular metabolites, hormonal signals and inflammatory mediators all contribute actively to cancer progression. Protein post-translational modification (PTM) is often regarded as a degradative mechanism in protein destruction or turnover to maintain physiological homeostasis. Advances in quantitative transcriptomics, proteomics, and nuclease-based gene editing are now paving the global ways for exploring PTMs. In this review, we focus on recent developments in the PTM area and speculate on their importance as a critical functional readout for the regulation of TME. A wealth of information has been emerging to prove useful in the search for conventional therapies and the development of global therapeutic strategies.

Fig. 1

Chemical structures of histone/nonhistone PTMs in this review

Fig. 2

Schematic representation of protein N-myristoylation and function. a The myristoylation of formin family protein FMNL1 leads to membrane association, membrane trafficking and bleb formation. b The N-terminal myristoylation is essential for the membrane attachment and kinase activity of Src. c The myristoylated TRAM tethers it to the membrane, serving as a prerequisite for LPS signaling. d Co-translational N-myristoylation. The initiator methionine is removed by methionine aminopeptidase 2 and myristic acid is transferred to the N-terminal glycine residue by NMT. e Post-translational N-myristoylation. Some proteins are cleaved by a protease to facilitate a myristic acid is covalently attached to glycine residue by NMT

Fig. 3

Ras is a membrane-associated guanine-nucleotide-binding protein that is normally activated in response to the binding of growth factors. Rac1 is a small G-protein in the Rho family that drives MTOC orientation, actin polymerization, and cell–cell adhesion. Rac1 is activated by ARHGEF6 and repressed by RacGAP in response to upstream regulators such as growth factors. Rho is a member of the Ras superfamily of small GTP-binding proteins that play a central role in diverse biological processes. Rho proteins cycle between an active GTP-bound state and an inactive GDP-bound state, which is controlled by regulatory proteins such as GEFs (guanine exchange factors and GAPs (GTPase-activating proteins). The GTPase RhoA plays a prominent role in regulating the organization of the cytoskeleton by promoting the assembly of focal adhesions and actin stress fibers and by activating FAK. PLD1 catalyzes the hydrolysis of phosphatidylcholine to yield phosphatidic acid and choline. Rho also activates scaffolding proteins such as GDIA and IRSp53 (insulin receptor substrate protein-53). RhoA also binds to Rho/philin and regulate the actin cytoskeleton. The Rho family members Rac1, RhoA, and CDC42 were reported geranylgeranylated, and Ras was reported farnesylated to regulate their cellular functions

Fig. 4

Biological effect of modification on tumor initiation and development. Five groups of PTMs function in cellular biological processes, including altering higher-order chromatin structures to positively or negatively regulate gene transcription, modulating protein attachment on membrane or transcription factors to regulate downstream signal transduction, changing metabolic enzymes and related transcription factors to regulate metabolic reprogramming, as well as remodeling cytoskeleton and cell adhesion system to regulate tumor invasion

Fig. 5

Overview of the hexosamine biosynthetic pathway (HBP) and the regulation of O-GlcNAcylation in TME. Left: O-GlcNAcylation orchestrates immunity. O-GlcNAcylation is increased after neutrophils are activated through the MAPK pathway. In macrophages, O-GlcNAcylation shows both activation and inhibition functions of NF-κB. Upon RNA virus infection, MAVS is modified by OGT to enhance downstream IFN production via IRF3 signaling. O-GlcNAcylation reduces the cytotoxic activity and inhibits NK differentiation by increasing the stability of EZH2. O-GlcNAcylation increases the expression of RORγt and FOXP3 in Th17 and Treg cells. NFAT and NFκB are activated by O-GlcNAcylation in activated B cells and O-GlcNAcylation of LSP1 contributes to B-cell apoptosis. After TCR rearrangement, O-GlcNAcylation promotes positive T-cell development. Middle: nutrient flux modulates protein O-GlcNAcylation. OGT catalyzes the addition of GlcNAc from UDP-GlcNAc to serine and threonine residues, while OGA catalyzes their removal. Right: the function of O-GlcNAcylation in proteasome-associated degradation, cytoskeleton remodeling, and transcriptional regulation

Fig. 6

Overview of a mature T-cell synapse. The immunological synapses (IS) is also termed supramolecular activation complexes (SMACs), including the central region of the supramolecular activation complex (c-SMAC), the peripheral ring surrounding the c-SMAC (p-SMAC), the region distal to the synapse outside the p-SMAC (d-SMAC) and the molecules/ligand pairs that are found enriched within. Protein myristoylation makes a significant contribution to IS formation. APC antigen-presenting cell, CTLA4 cytotoxic T-lymphocyte antigen 4, ICAM1 intercellular adhesion molecule 1, LFA1 leukocyte function-associated antigen 1, PI3K phosphatidylinositol 3-kinase, SHP2 SRC homology 2-domain-containing protein tyrosine phosphatase 2, TCR T-cell receptor, ZAP70 ζ-chain-associated protein 70, LCK Src-family kinase

Fig. 7

The modification of ubiquitination, palmitoylation, and glycosylation of the programmed cell death ligand 1 (PD-L1) protein