TY - JOUR
T1 - Mieap-regulated mitochondrial quality control is frequently inactivated in human colorectal cancer
AU - Kamino, H.
AU - Nakamura, Y.
AU - Tsuneki, M.
AU - Sano, H.
AU - Miyamoto, Y.
AU - Kitamura, N.
AU - Futamura, M.
AU - Kanai, Y.
AU - Taniguchi, H.
AU - Shida, D.
AU - Kanemitsu, Y.
AU - Moriya, Y.
AU - Yoshida, K.
AU - Arakawa, H.
AU - Zheng, M.
AU - Turton, K. B.
AU - Zhu, F.
AU - Li, Y.
AU - Grindle, K. M.
AU - Annis, D. S.
AU - Lu, L.
AU - Drennan, A. C.
AU - Tweardy, D. J.
AU - Bharadwaj, U.
AU - Mosher, D. F.
AU - Rui, L.
N1 - Funding Information:
We thank Yoko Sagami for technical assistance. This work was supported in part by the Japan Society for the Promotion of Science KAKENHI Grant numbers 24240117 (to HA), 22501021 (to YN), 23659178 (to HA), 25430124 (to YN), 25430125 (to HK), 25670169 (to HA); by the Ministry of Health, Labour and Welfare for the Practical Research for Innovative Cancer H26-practical-general-001 (to HA); by the National Cancer Center Research and Development Fund Grant numbers 23-B-7 (to HA); and by the Japan Agency for Medical Research and Development AMED Grant number 15ck0106006h0002 (to HA).
Publisher Copyright:
© 2016, Nature Publishing Group. All rights reserved.
PY - 2016/1/4
Y1 - 2016/1/4
N2 - Mieap, a p53-inducible protein, controls mitochondrial quality by repairing or eliminating unhealthy mitochondria. BNIP3 and NIX are critical mediators for the Mieap-regulated mitochondrial quality control. Mieap suppresses murine intestinal tumor via its mitochondrial quality control function. To explore the role of the Mieap-regulated mitochondria quality control function in colorectal cancer patients, we examined the statuses of p53, Mieap, BNIP3 and NIX in 57 primary colorectal cancer tissues. Promoter methylation of the Mieap and BNIP3 genes was found in 9% and 47% of colorectal cancer cases, respectively, whereas p53 mutation was found in more than 50% of colorectal cancer tissues lacking methylation of the Mieap and BNIP3 promoters, implying that the p53/Mieap/BNIP3-regulated mitochondria quality control pathway is inactivated in more than 70% of colorectal cancer patients. In LS174T colorectal cancer cells, hypoxia activated the Mieap-regulated mitochondria quality control function. Knockdown of p53, Mieap or BNIP3 in LS174T cells severely impaired the hypoxia-activated function, leading to the accumulation of unhealthy mitochondria and increase of mitochondrial reactive oxygen species generation. The mitochondrial reactive oxygen species generated by unhealthy mitochondria in the p53/Mieap/BNIP3-deficient cells remarkably enhanced cancer cell migration and invasion under hypoxic condition. These results suggest that the Mieap-regulated mitochondria quality control has a critical role in colorectal cancer suppression in the in vivo hypoxic tumor microenvironment.
AB - Mieap, a p53-inducible protein, controls mitochondrial quality by repairing or eliminating unhealthy mitochondria. BNIP3 and NIX are critical mediators for the Mieap-regulated mitochondrial quality control. Mieap suppresses murine intestinal tumor via its mitochondrial quality control function. To explore the role of the Mieap-regulated mitochondria quality control function in colorectal cancer patients, we examined the statuses of p53, Mieap, BNIP3 and NIX in 57 primary colorectal cancer tissues. Promoter methylation of the Mieap and BNIP3 genes was found in 9% and 47% of colorectal cancer cases, respectively, whereas p53 mutation was found in more than 50% of colorectal cancer tissues lacking methylation of the Mieap and BNIP3 promoters, implying that the p53/Mieap/BNIP3-regulated mitochondria quality control pathway is inactivated in more than 70% of colorectal cancer patients. In LS174T colorectal cancer cells, hypoxia activated the Mieap-regulated mitochondria quality control function. Knockdown of p53, Mieap or BNIP3 in LS174T cells severely impaired the hypoxia-activated function, leading to the accumulation of unhealthy mitochondria and increase of mitochondrial reactive oxygen species generation. The mitochondrial reactive oxygen species generated by unhealthy mitochondria in the p53/Mieap/BNIP3-deficient cells remarkably enhanced cancer cell migration and invasion under hypoxic condition. These results suggest that the Mieap-regulated mitochondria quality control has a critical role in colorectal cancer suppression in the in vivo hypoxic tumor microenvironment.
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U2 - 10.1038/oncsis.2015.43
DO - 10.1038/oncsis.2015.43
M3 - Article
AN - SCOPUS:84953869926
SN - 2157-9024
VL - 5
SP - e181
JO - Oncogenesis
JF - Oncogenesis
ER -
