HTLV-1 bZIP Factor-Induced Reprogramming of Lactate Metabolism and Epigenetic Status Promote Leukemic Cell Expansion
-
- Kosuke Toyoda
- 1Department of Hematology, Rheumatology, and Infectious Disease, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
-
- Jun-ichirou Yasunaga
- 1Department of Hematology, Rheumatology, and Infectious Disease, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
-
- Takafumi Shichijo
- 1Department of Hematology, Rheumatology, and Infectious Disease, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
-
- Yuichiro Arima
- 2Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
-
- Kenichi Tsujita
- 2Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
-
- Azusa Tanaka
- 5Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
-
- Tarig Salah
- 1Department of Hematology, Rheumatology, and Infectious Disease, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
-
- Wenyi Zhang
- 1Department of Hematology, Rheumatology, and Infectious Disease, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
-
- Osama Hussein
- 1Department of Hematology, Rheumatology, and Infectious Disease, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
-
- Miyu Sonoda
- 1Department of Hematology, Rheumatology, and Infectious Disease, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
-
- Miho Watanabe
- 1Department of Hematology, Rheumatology, and Infectious Disease, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
-
- Daisuke Kurita
- 1Department of Hematology, Rheumatology, and Infectious Disease, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
-
- Kazutaka Nakashima
- 6Department of Pathology, Kurume University School of Medicine, Fukuoka, Japan.
-
- Kyohei Yamada
- 6Department of Pathology, Kurume University School of Medicine, Fukuoka, Japan.
-
- Hiroaki Miyoshi
- 6Department of Pathology, Kurume University School of Medicine, Fukuoka, Japan.
-
- Koichi Ohshima
- 6Department of Pathology, Kurume University School of Medicine, Fukuoka, Japan.
-
- Masao Matsuoka
- 1Department of Hematology, Rheumatology, and Infectious Disease, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
説明
<jats:title>Abstract</jats:title> <jats:sec> <jats:title /> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Significance:</jats:title> <jats:p>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.</jats:p> <jats:p>This article is featured in Selected Articles from This Issue, p. 337</jats:p> </jats:sec>
収録刊行物
-
- Blood Cancer Discovery
-
Blood Cancer Discovery 4 (5), 374-393, 2023-05-09
American Association for Cancer Research (AACR)
- Tweet
詳細情報 詳細情報について
-
- CRID
- 1360298757173549824
-
- ISSN
- 26433249
- 26433230
-
- Web Site
- https://aacrjournals.org/bloodcancerdiscov/article-pdf/doi/10.1158/2643-3230.BCD-22-0139/3330252/bcd-22-0139.pdf
- https://aacrjournals.org/bloodcancerdiscov/article-pdf/doi/10.1158/2643-3230.BCD-22-0139/3351086/bcd-22-0139.pdf
- https://aacrjournals.org/bloodcancerdiscov/article-pdf/4/5/374/3408446/374.pdf
-
- データソース種別
-
- Crossref
- KAKEN