Regulation of Cancer Metabolism by Deubiquitinating Enzymes: The Warburg Effect

Abstract

Cancer is a disorder of cell growth and proliferation, characterized by different metabolic pathways within normal cells. The Warburg effect is a major metabolic process in cancer cells that affects the cellular responses, such as proliferation and apoptosis. Various signaling factors down/upregulate factors of the glycolysis pathway in cancer cells, and these signaling factors are ubiquitinated/deubiquitinated via the ubiquitin–proteasome system (UPS). Depending on the target protein, DUBs act as both an oncoprotein and a tumor suppressor. Since the degradation of tumor suppressors and stabilization of oncoproteins by either negative regulation by E3 ligases or positive regulation of DUBs, respectively, promote tumorigenesis, it is necessary to suppress these DUBs by applying appropriate inhibitors or small molecules. Therefore, we propose that the DUBs and their inhibitors related to the Warburg effect are potential anticancer targets.

Transforming Growth Factor-β: An Agent of Change in the Tumor Microenvironment

“…In general, TGF-β shifts metabolism from mitochondrial oxidative phosphorylation toward a ketogenic metabolism, and EMT and EndMT, which are induced by TGF-β, can shift tumor and endothelial cell metabolism from oxidative phosphorylation toward anaerobic glycolysis (Angioni et al, 2021). Such a switching of the tumor metabolism from oxidative phosphorylation to anerobic glycolysis and lactate production was first described by Warburg (Warburg et al, 1927;Kim and Baek, 2021).…”

Acute Myeloid Leukemia-Related Proteins Modified by Ubiquitin and Ubiquitin-like Proteins

“…Deubiquitination is the reverse process of ubiquitination, is mediated by DUBs. DUBs are the most studied DCEs comprising of: ubiquitin-specific proteases (USP), ubiquitin C-terminal hydrolases (UCH), otubain domain ubiquitin-binding proteins (OTU), Machado–Joseph disease protein domain proteases (MJD), the MIU-containing novel DUB family (MINDY), the monocyte chemotactic protein-induced proteins (MCPIP) families, the Zn-finger and UFSP domain protein (ZUFSP) family, the permuted papain fold peptidase of dsDNA viruses and eukaryotes (PPPDE), and the Jab1/MPN domain-associated metalloisopeptidase (JAMM) family [ 84 , 85 ]. Depending on their enzymatic cleavage mechanism, DUBs are classified into two types: cysteine protease and metalloprotease.…”

Methylosystem for Cancer Sieging Strategy

“…In this malignant mechanism, the MYC oncogene contributes to alterations in cellular metabolism to facilitate tumorigenesis by altering nucleotide metabolism and DNA replication induced by the attenuated expression of E2F1; hypoxia-inducible transcription factor 1; lactate dehydrogenase A; and several microRNAs, such as miR-23a/b, to increase the protein expression of glutaminase [15]. In addition to the regulation of gene expression at the transcriptional level, research has revealed the significance of the ubiquitin-proteasome system (UPS), which controls various signaling factors in the glycolysis pathway via ubiquitination or deubiquitination [16]. As a result of UPS, deubiquitination acts as either a tumor-promoting oncoprotein or as a tumor-restricting suppressor protein [16].…”

“…In addition to the regulation of gene expression at the transcriptional level, research has revealed the significance of the ubiquitin-proteasome system (UPS), which controls various signaling factors in the glycolysis pathway via ubiquitination or deubiquitination [16]. As a result of UPS, deubiquitination acts as either a tumor-promoting oncoprotein or as a tumor-restricting suppressor protein [16].…”