Table 3.

Examples of key proteins with its corresponding post-translational modification(s) (in bold) related to cancer hallmarks/responsible for cancer pathophysiology.

Protein Name	Type of PTM(s) involved
Programmed Death-Ligand 1 (PD-L1/CD274)	Epigenetic modifications, such as histone acetylation and methylation of H3K3me3. - Histone acetylation helps BET domain proteins (BRD4) to associate with PD-L1. Also, HDAC inhibitors augment histone acetylation and upregulate PD-L1 expression in tumors (28–30). - Trimethylation of histone H3 on lysine 4 increases PD-L1 expression in cancer cells. For example, Histone methyltransferase (HMTase) MLL1 associate with CD274 promoter and catalyzes H3K4me3, thereby upregulating its expression, which in turn boosts PD-L1 mRNA levels in tumors (31).
N-acetylgalactosaminyltransferases (GALNTs)	GALNTs are group of enzymes that are responsible at modulating initial mucin-type O-glycosylation, which have shown close relationship with cancer incidence and metastasis (4, 5). Previous animal studies have extensively reported that GALNT class of enzymes (GALNT1-GALNT20) act as prognostic markers for different cancers, or have been linked to alterations in cellular characteristics including cell proliferation, migration, invasion and metastasis in experimental models (6). Few of the broad range of cancers in which altered protein levels of GALNTs have been demonstrated include colorectal (7), gastric (8), breast (9), pancreatic (10), lung adenocarcinoma (11), NSCLC (12), and glioma (13). Studies showed that GALNT2 promotes tumor formation and progression in BALB/c nude mice models (14). Many transmembrane proteins are modified by N-linked glycosylation, which is responsible for tumor metastasis. This study also demonstrates that N-glycosylation of T-cell membrane protein-4 (TIM-4) at Asn291 site is conducive to cancer metastasis as reported in vitro and in vivo models (15).
Prohibitin (PHB)	PHBs (PHB1 and PHB2) are evolutionary conserved scaffold proteins that are ubiquitously expressed in mitochondria, plasma membrane and nucleus. They exhibit diverse compartment-specific regulatory roles such as cell proliferation, metabolism, lipid scaffolding in cell membrane, mitochondrial remodeling, and apoptosis (32–35). PHBs play an important role in carcinogenesis by regulating vital cellular signaling pathways (such as the Ras-Raf-MEK-ERK signaling axis) that leads to cell proliferation, and metastasis and these proteins are tightly controlled by phosphorylation ( 36, 37). In bladder cancer (BCa), the expression levels of PHB1 were found to be higher (in 141 out of 167 patients), indicating that PHB1 is required for BCa cell proliferation (38). Another report demonstrated that mitochondrial localization of PHB is regulated by Protein Kinase B (PKB)/Akt-mediated phosphorylation of Prohibitin at Thr258 site (in the cytoplasm) in BCa patients. Thus, phosphorylated-PHB is a suitable therapeutic target in BCa (39). Besides, phosphorylation of PHB1 at Ser121, Tyr259, and Tyr114 regions is also responsible for tumor formation (40, 41).
MYC (c-MYC/N-MYC/L-MYC)	The oncoprotein MYC is a pleiotropic transcription factor that affects essential cellular functions such as proliferation, differentiation, cell cycle, metabolism, and apoptosis (23). Strong evidence defines both aberrant MYC expression as an oncogenic driver of malignancies as well as its association to all of cancer ‘hallmarks’ (42, 43). Surprisingly, MYC allows tumor cells to escape immune-surveillance either by downregulating MHCI expression or by upregulating inhibitory cytokines and immune-checkpoint proteins such as PD-L1 and CD47, thereby shedding light on associating MYC inhibition and escape of immune-checkpoints to target MYC (44–46).
Fructose-1,6-bisphosphatase (FBP-1)	Fructose-1,6-bisphosphatase (FBP-1 or FBPase) is a rate-limiting enzyme catalyzing the conversion of fructose 1,6-bisphosphate to fructose 6-phosphate and inorganic phosphate, which is an important step in gluconeogenesis, required for the regulation of energy metabolism and maintenance of glucose homeostasis (47). Evidences support that FBP-1 downregulation is considered to be as a prognostic cancer marker for different tumor types such as gastric cancer, lung cancer and breast cancer, increasing the glycolytic rate and cancer stem cells in number (48–50). Recent reports demonstrated that TRIM28, which is an E3 Ubiquitin ligase, helps in regulation of FBP-1 expression levels by some post-translational changes in hepatic cancer. Furthermore, it was observed that TRIM28 directly associate with and recruits to ubiquitination by degrading FBP1 protein. Direct interacting partners of TRIM28 such as MAGE-A3 and MAGE-C2 (51, 52), can augment TRIM28-specific degradation of FBP1 by forming a ternary ubiquitin ligase complexes with TRIM28 (53).
Heat shock protein 90 (HSP90)	HSP90 is an evolutionarily conserved molecular chaperone that participates in cellular homeostasis and is an important mediator of oncogene addiction (54, 55). Studies showed that NO-dependent nitrosylation at Cys597 position in C domain of HSP90 blocks chaperone function in endothelial cell lines (56). Existing findings about anti-cancerous activity of externally administered NO may have been caused from its blockade of HSP90 in tumors (57), which is consistent with the observations that HSP90 in regulation of telomeric activity (58).