TIP60 is required for tumorigenesis in non‐small cell lung cancer

• Published in: Cancer science Vol. 114; no. 6; pp. 2400 - 2413
• Main Authors: 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, Kobayashi, Susumu S.
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.06.2023; John Wiley and Sons Inc
• Subjects: Acetyltransferase; Animals; Antitumor activity; artemisinin; Cancer therapies; Carcinogenesis - genetics; Carcinoma, Non-Small-Cell Lung - genetics; Cell adhesion & migration; Cell culture; Cell growth; Cell migration; Cell Transformation, Neoplastic - genetics; Cloning; Comparative analysis; Datasets; Epigenetics; Experiments; Histone Acetyltransferases - genetics; Histone Acetyltransferases - metabolism; Histones; Homeostasis; Humans; Hypotheses; KAT5; Kinases; Lung cancer; Lung Neoplasms - genetics; Mice; Mutation; Non-small cell lung carcinoma; Original; Prostate; Proteins; Sarcoma; Small cell lung carcinoma; TGM5; TIP60; Transcription activation; Tumor cell lines; Tumorigenesis; Wound healing; artemisinin; lung cancer; KAT5; TGM5; TIP60
• ISSN: 1347-9032; 1349-7006; 1349-7006
• DOI: 10.1111/cas.15785

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. Genetic and pharmacological inhibition of TIP60 attenuates tumorigenesis in non‐small cell lung cancer, implicating that targeting TIP60 could be a novel approach for lung cancer treatment.