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

Aberrant regulation of ubiquitination often leads to metabolic reprogramming in tumor cells. However, the underlying mechanisms are not fully understood. Here we demonstrate that OTUB2, an OTU deubiquitinase, is upregulated in colorectal cancer (CRC) and exacerbates the progression of CRC through modulating the aerobic glycolysis. Mechanistically, OTUB2 directly interacts with pyruvate kinase M2 (PKM2) and inhibits its ubiquitination by blocking the interaction between PKM2 and its ubiquitin E3 ligase Parkin, thereby enhancing PKM2 activity and promoting glycolysis. In response to glucose starvation stress, the effect of OTUB2 on PKM2 is enhanced, which confers metabolic advantage to CRC cells. Moreover, OTUB2 depletion reduces glucose consumption, lactate production, and cellular ATP production. OTUB2-knockout CRC cells exhibit attenuated proliferation and migration, as well as an elevated level of apoptosis and increased sensitivity to chemotherapy drugs. Furthermore, in vivo assays show that knockout of OTUB2 inhibits tumor growth in mice. Taken together, these findings reveal the critical role of OTUB2 in the regulation of glycolysis and illustrate the molecular mechanism underlying its role as a negative regulator of PKM2 ubiquitination in CRC, establishing a bridge between OTUB2-regulated PKM2 ubiquitination and altered metabolic patterns in CRC and suggesting that OTUB2 is a promising target for CRC treatment.