American Association for Cancer Research
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Figure S5 from HTLV-1 bZIP Factor-Induced Reprogramming of Lactate Metabolism and Epigenetic Status Promote Leukemic Cell Expansion

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journal contribution
posted on 2023-07-27, 15:00 authored by Kosuke Toyoda, Jun-ichirou Yasunaga, Takafumi Shichijo, Yuichiro Arima, Kenichi Tsujita, Azusa Tanaka, Tarig Salah, Wenyi Zhang, Osama Hussein, Miyu Sonoda, Miho Watanabe, Daisuke Kurita, Kazutaka Nakashima, Kyohei Yamada, Hiroaki Miyoshi, Koichi Ohshima, Masao Matsuoka

Transcriptional regulation of SLC16A1 and SLC16A3 by TAp73, and mRNA expression levels of MCT-coding genes among various cancers.



Acceleration of glycolysis is a common trait of cancer. A key metabolite, lactate, is typically secreted from cancer cells because 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 the 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. An antisense gene encoded in HTLV-1, HBZ, reprograms lactate metabolism and epigenetic modification by inducing TAp73 in virus-positive leukemic cells. A positive correlation between TAp73 and its target genes is also observed in many other cancer cells, suggesting that this is a common mechanism for cellular oncogenesis.

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