Deubiquitinase OTUB2 exacerbates the progression of colorectal cancer by promoting PKM2 activity and glycolysis

Long non‐coding RNA VAL facilitates PKM2 enzymatic activity to promote glycolysis and malignancy of gastric cancer

“…Recently, accumulated studies have elucidated that ubiquitination/deubiquitination post‐translational modification system functions as an important approach to regulate metabolic reprogramming and metabolic enzymes in diverse cancer types. 37 , 38 , 39 Despite E3 ligases, like FBXW7, Malin and Nedd4, 40 , 41 , 42 and deubiquitinase, like PSMD14, 43 are involved in regulating ubiquitination and proteasome‐dependent degradation of PKM2, the E3 ligase Parkin‐mediated PKM2 ubiquitination markedly abrogates the enzymatic activity of PKM2 without an effect on its protein stability, which may be reversed by deubiquitinase OTUB2, 34 , 35 suggesting that the regulatory mechanism on PKM2 enzymatic activity and expression level by ubiquitination is complex and largely context‐dependent. Therefore, the core factors being critical for modulating the biological function of PKM2 in GCs remain to be explored.…”

Non-proteolytic ubiquitylation in cellular signaling and human disease

“…Targeting the HECTH9-HK2 signaling could emerge as an effective strategy to limit CSC expansion and cancer progression in metabolism-addicted tumors. The importance of non-proteolytic ubiquitylation in the metabolic reprogramming of tumor cells has also been confirmed by another recent study which reported a role for the DUB OTUB2 in promoting colorectal cancer progression by elevating the Pyruvate kinase M2 (PKM2) enzymatic activity, subsequently upregulating glycolysis 139 Upon conditions of nutrient deficiency, OTUB2 co-localizes and interacts with PKM2 in the cytoplasm and blocks its ubiquitylation. Interestingly, this interaction occurs independently of OTUB2 catalytic activity but is instead mediated via competing with the E3 ligase Parkin 140 for binding to PKM2, highlighting the significance of monitoring the balance between ubiquitylation/deubiquitylation events on key metabolic enzymes as a means to understand how cancer cells respond to metabolic stress (Fig.…”

N6-methyladenosine methyltransferase KIAA1429 elevates colorectal cancer aerobic glycolysis via HK2-dependent manner

“…Energy metabolism, especially aerobic glycolysis (also known as Warburg effect), plays critical role in CRC tumorigenesis. For example, OTUB2 negatively regulates PKM2 ubiquitination and the depletion of OTUB2 reduces the glucose consumption, lactate production and cellular ATP production, exhibiting attenuated proliferation and migration and increased sensitivity to chemotherapy drugs for CRC [ 18 ]. In CRC, NDRG2 inhibits the cellular proliferation, reduces glucose uptake and decreases key glycolysis enzymes expression through promoting the occupancy of transcription factor Mondo A on TXNIP promoter and the suppression of C-myc [ 19 ].…”