HTLV-1 bZIP factor-induced reprogramming of lactate metabolism and epigenetic status promote leukemic cell expansion

by Selleckchem | Sep 26 2023

Acceleration of glycolysis is a common trait of cancer. A key metabolite, lactate, is typically secreted from cancer cells, since its accumulation is toxic. Here, we report that a viral oncogene, HTLV-1 bZIP factor (HBZ), bimodally upregulates TAp73 to promote lactate excretion from adult T-cell leukemia-lymphoma (ATL) cells. HBZ protein binds to EZH2 and reduces its occupancy of the TAp73 promoter. Meanwhile, HBZ RNA activates TAp73 transcription via the BATF3-IRF4 machinery. TAp73 upregulates the lactate transporters MCT1 and MCT4. Inactivation of TAp73 leads to intracellular accumulation of lactate, inducing cell death in ATL cells. Furthermore, TAp73 knockout diminishes development of inflammation in HBZ-transgenic mice. An MCT1/4 inhibitor, syrosingopine, decreases the growth of ATL cells in vitro and in vivo. MCT1/4 expression is positively correlated with TAp73 in many cancers, and MCT1/4 upregulation is associated with dismal prognosis. Activation of the TAp73-MCT1/4 pathway could be a common mechanism contributing to cancer metabolism.

Comments:

The passage you provided discusses the role of the viral oncogene HTLV-1 bZIP factor (HBZ) in upregulating TAp73 and promoting lactate excretion in adult T-cell leukemia-lymphoma (ATL) cells. The acceleration of glycolysis, a process that generates energy through the breakdown of glucose, is a common trait of cancer cells. However, the accumulation of lactate, a byproduct of glycolysis, is toxic to cells. Therefore, cancer cells typically secrete lactate to prevent its buildup.

The study suggests that HBZ plays a role in the regulation of lactate excretion in ATL cells. The HBZ protein interacts with EZH2, a protein involved in gene regulation, and reduces its binding to the TAp73 promoter. TAp73 is a transcription factor that is bimodally upregulated by HBZ RNA through the BATF3-IRF4 machinery, a complex involved in gene expression. TAp73, in turn, upregulates the expression of lactate transporters MCT1 and MCT4, which facilitate the export of lactate from cells.

Inactivation of TAp73 leads to the accumulation of lactate within ATL cells, resulting in cell death. Additionally, the study found that knockout of TAp73 in HBZ-transgenic mice diminished the development of inflammation. Furthermore, an inhibitor of MCT1/4, called syrosingopine, decreased the growth of ATL cells both in vitro and in vivo. The expression of MCT1/4 is positively correlated with TAp73 in many cancers, and increased expression of MCT1/4 is associated with a poor prognosis.

Overall, the findings suggest that activation of the TAp73-MCT1/4 pathway could be a common mechanism contributing to cancer metabolism, including the acceleration of glycolysis and lactate excretion. Targeting this pathway, such as inhibiting MCT1/4, may have potential therapeutic implications for cancers that rely on this metabolic pathway.