@article{55119fc13aba4d209af8e701714be374,
title = "ZBTB2 links p53 deficiency to HIF-1-mediated hypoxia signaling to promote cancer aggressiveness",
abstract = "Aberrant activation of the hypoxia-inducible transcription factor HIF-1 and dysfunction of the tumor suppressor p53 have been reported to induce malignant phenotypes and therapy resistance of cancers. However, their mechanistic and functional relationship remains largely unknown. Here, we reveal a mechanism by which p53 deficiency triggers the activation of HIF-1-dependent hypoxia signaling and identify zinc finger and BTB domain-containing protein 2 (ZBTB2) as an important mediator. ZBTB2 forms homodimers via its N-terminus region and increases the transactivation activity of HIF-1 only when functional p53 is absent. The ZBTB2 homodimer facilitates invasion, distant metastasis, and growth of p53-deficient, but not p53-proficient, cancers. The intratumoral expression levels of ZBTB2 are associated with poor prognosis in lung cancer patients. ZBTB2 N-terminus-mimetic polypeptides competitively inhibit ZBTB2 homodimerization and significantly suppress the ZBTB2–HIF-1 axis, leading to antitumor effects. Our data reveal an important link between aberrant activation of hypoxia signaling and loss of a tumor suppressor and provide a rationale for targeting a key mediator, ZBTB2, to suppress cancer aggressiveness.",
keywords = "HIF-1, ZBTB2, cancer, hypoxia, p53",
author = "Sho Koyasu and Shoichiro Horita and Keisuke Saito and Minoru Kobayashi and Hiroshi Ishikita and Chow, {Christalle C.T.} and Gouki Kambe and Shigeto Nishikawa and Toshi Menju and Akiyo Morinibu and Yasushi Okochi and Yoshiaki Tabuchi and Yasuhito Onodera and Norihiko Takeda and Hiroshi Date and Semenza, {Gregg L.} and Hammond, {Ester M.} and Hiroshi Harada",
note = "Funding Information: We would like to thank Prof. Hiroyuki Kouji, Oita University, for his critical suggestions and helpful discussion about the protein structure of ZBTB2, Prof. Masahiro Sonoshita, Hokkaido University, for technical advice, and Ms. Kumi Johchi and Ms. Sawako Hayami for technical assistance. This study was supported by the Research Project on Development of New Drugs (17933766), the Translational Research Grant Seeds A (A101), the AMED‐CREST (21gm1110010s0203), and the Promotion of Cancer Research and Therapeutic Evolution (P‐PROMOTE; 22ama221417h0001) to H.H. from the Japan Agency for Medical Research and development (AMED), by the Core‐to‐Core Program (JPJSCCA20200009) to H.H. and KAKENHI (18KK0241, 19K22595, 20H03621, 20H05033, 21KK0144, and 21K19445 to H.H., 21K07727 to M.K., and 16H06891, 17J07699, and 19K17164 to S.K.) from the Japan Society for the Promotion of Science (JSPS), and by the research grant programs of the Princess Takamatsu Cancer Research Fund, Uehara Memorial Foundation, Takeda Science Foundation, Ichiro Kanehara Foundation for the Promotion of Medical Sciences and Medical Care, Kobayashi Foundation for Cancer Research, Yasuda Medical Foundation, and the Foundation for Promotion of Cancer Research to H.H. This study was conducted through the Joint Usage Programs of the Radiation Biology Center, Kyoto University, and of the Institute for Integrated Radiation and Nuclear Science, Kyoto University. S.K. was a JSPS postdoctoral research fellow, SPD. Funding Information: We would like to thank Prof. Hiroyuki Kouji, Oita University, for his critical suggestions and helpful discussion about the protein structure of ZBTB2, Prof. Masahiro Sonoshita, Hokkaido University, for technical advice, and Ms. Kumi Johchi and Ms. Sawako Hayami for technical assistance. This study was supported by the Research Project on Development of New Drugs (17933766), the Translational Research Grant Seeds A (A101), the AMED-CREST (21gm1110010s0203), and the Promotion of Cancer Research and Therapeutic Evolution (P-PROMOTE; 22ama221417h0001) to H.H. from the Japan Agency for Medical Research and development (AMED), by the Core-to-Core Program (JPJSCCA20200009) to H.H. and KAKENHI (18KK0241, 19K22595, 20H03621, 20H05033, 21KK0144, and 21K19445 to H.H., 21K07727 to M.K., and 16H06891, 17J07699, and 19K17164 to S.K.) from the Japan Society for the Promotion of Science (JSPS), and by the research grant programs of the Princess Takamatsu Cancer Research Fund, Uehara Memorial Foundation, Takeda Science Foundation, Ichiro Kanehara Foundation for the Promotion of Medical Sciences and Medical Care, Kobayashi Foundation for Cancer Research, Yasuda Medical Foundation, and the Foundation for Promotion of Cancer Research to H.H. This study was conducted through the Joint Usage Programs of the Radiation Biology Center, Kyoto University, and of the Institute for Integrated Radiation and Nuclear Science, Kyoto University. S.K. was a JSPS postdoctoral research fellow, SPD. Publisher Copyright: {\textcopyright} 2022 The Authors.",
year = "2023",
month = jan,
day = "9",
doi = "10.15252/embr.202154042",
language = "English (US)",
volume = "24",
journal = "EMBO Reports",
issn = "1469-221X",
publisher = "Nature Publishing Group",
number = "1",
}