1. TIP60 is required for tumorigenesis in non‐small cell lung cancer
- Author
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Shibahara, Daisuke, Akanuma, Naoki, Kobayashi, Ikei S, Heo, Eunyoung, Ando, Mariko, Fujii, Masanori, Jiang, Feng, Prin, P Nicholas, Pan, Gilbert, Wong, Kwok‐Kin, Costa, Daniel B, Bararia, Deepak, Tenen, Daniel G, Watanabe, Hideo, and Kobayashi, Susumu S
- Subjects
Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Biotechnology ,Cancer ,Lung Cancer ,Genetics ,Lung ,2.1 Biological and endogenous factors ,Aetiology ,Animals ,Mice ,Carcinogenesis ,Carcinoma ,Non-Small-Cell Lung ,Cell Transformation ,Neoplastic ,Histone Acetyltransferases ,Lung Neoplasms ,Humans ,artemisinin ,KAT5 ,lung cancer ,TGM5 ,TIP60 ,Pharmacology and Pharmaceutical Sciences ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
Histone modifications play crucial roles in transcriptional activation, and aberrant epigenetic changes are associated with oncogenesis. Lysine (K) acetyltransferases 5 (TIP60, also known as KAT5) is reportedly implicated in cancer development and maintenance, although its function in lung cancer remains controversial. Here we demonstrate that TIP60 knockdown in non-small cell lung cancer cell lines decreased tumor cell growth, migration, and invasion. Furthermore, analysis of a mouse lung cancer model with lung-specific conditional Tip60 knockout revealed suppressed tumor formation relative to controls, but no apparent effects on normal lung homeostasis. RNA-seq and ChIP-seq analyses of inducible TIP60 knockdown H1975 cells relative to controls revealed transglutaminase enzyme (TGM5) as downstream of TIP60. Investigation of a connectivity map database identified several candidate compounds that decrease TIP60 mRNA, one that suppressed tumor growth in cell culture and in vivo. In addition, TH1834, a TIP60 acetyltransferase inhibitor, showed comparable antitumor effects in cell culture and in vivo. Taken together, suppression of TIP60 activity shows tumor-specific efficacy against lung cancer, with no overt effect on normal tissues. Our work suggests that targeting TIP60 could be a promising approach to treating lung cancer.
- Published
- 2023