HTLV-1 bZIP Factor-Induced Reprogramming of Lactate Metabolism and Epigenetic Status Promote Leukemic Cell Expansion

Area of Science:

• Oncology
• Molecular Biology
• Virology

Background:

• Cancer cells exhibit accelerated glycolysis, producing lactate.
• Lactate accumulation is toxic, necessitating its secretion from cancer cells.
• The human T-cell leukemia virus type 1 (HTLV-1) bZIP factor (HBZ) is implicated in cancer development.

Purpose of the Study:

• To investigate the role of HBZ in regulating lactate metabolism in adult T-cell leukemia-lymphoma (ATL) cells.
• To elucidate the mechanism by which HBZ influences lactate excretion and cancer cell survival.
• To explore the therapeutic potential of targeting the identified pathway.

Main Methods:

• Investigated the interaction between HBZ and EZH2.
• Analyzed HBZ RNA's effect on TAp73 transcription via the BATF3-IRF4 pathway.
• Assessed the role of TAp73 in regulating lactate transporters MCT1 and MCT4.
• Utilized TAp73 knockout and HBZ-transgenic mouse models.
• Examined the effect of an MCT1/4 inhibitor (syrosingopine) on ATL cell growth.

Main Results:

• HBZ bimodal upregulation of TAp73 promotes lactate excretion in ATL cells.
• HBZ modulates TAp73 expression through both protein-EZH2 interaction and RNA-mediated transcription.
• TAp73 activation leads to increased MCT1/4 expression, facilitating lactate transport.
• Inactivation of TAp73 causes lactate accumulation and cell death in ATL cells.
• Targeting MCT1/4 with syrosingopine inhibits ATL cell growth in vitro and in vivo.

Conclusions:

• The HBZ-TAp73-MCT1/4 axis is a key mechanism for lactate metabolism reprogramming in ATL.
• This pathway's activation is associated with poor prognosis in various cancers, suggesting a common oncogenic mechanism.
• Targeting the TAp73-MCT1/4 pathway represents a potential therapeutic strategy for cancers driven by this mechanism.