TY - JOUR
T1 - P62/Sqstm1 promotes malignancy of HCV-positive hepatocellular carcinoma through Nrf2-dependent metabolic reprogramming
AU - Saito, Tetsuya
AU - Ichimura, Yoshinobu
AU - Taguchi, Keiko
AU - Suzuki, Takafumi
AU - Mizushima, Tsunehiro
AU - Takagi, Kenji
AU - Hirose, Yuki
AU - Nagahashi, Masayuki
AU - Iso, Tetsuro
AU - Fukutomi, Toshiaki
AU - Ohishi, Maki
AU - Endo, Keiko
AU - Uemura, Takefumi
AU - Nishito, Yasumasa
AU - Okuda, Shujiro
AU - Obata, Miki
AU - Kouno, Tsuguka
AU - Imamura, Riyo
AU - Tada, Yukio
AU - Obata, Rika
AU - Yasuda, Daisuke
AU - Takahashi, Kyoko
AU - Fujimura, Tsutomu
AU - Pi, Jingbo
AU - Lee, Myung Shik
AU - Ueno, Takashi
AU - Ohe, Tomoyuki
AU - Mashino, Tadahiko
AU - Wakai, Toshifumi
AU - Kojima, Hirotatsu
AU - Okabe, Takayoshi
AU - Nagano, Tetsuo
AU - Motohashi, Hozumi
AU - Waguri, Satoshi
AU - Soga, Tomoyoshi
AU - Yamamoto, Masayuki
AU - Tanaka, Keiji
AU - Komatsu, Masaaki
PY - 2016/6/27
Y1 - 2016/6/27
N2 - p62/Sqstm1 is a multifunctional protein involved in cell survival, growth and death, that is degraded by autophagy. Amplification of the p62/Sqstm1 gene, and aberrant accumulation and phosphorylation of p62/Sqstm1, have been implicated in tumour development. Herein, we reveal the molecular mechanism of p62/Sqstm1-dependent malignant progression, and suggest that molecular targeting of p62/Sqstm1 represents a potential chemotherapeutic approach against hepatocellular carcinoma (HCC). Phosphorylation of p62/Sqstm1 at Ser349 directs glucose to the glucuronate pathway, and glutamine towards glutathione synthesis through activation of the transcription factor Nrf2. These changes provide HCC cells with tolerance to anti-cancer drugs and proliferation potency. Phosphorylated p62/Sqstm1 accumulates in tumour regions positive for hepatitis C virus (HCV). An inhibitor of phosphorylated p62-dependent Nrf2 activation suppresses the proliferation and anticancer agent tolerance of HCC. Our data indicate that this Nrf2 inhibitor could be used to make cancer cells less resistant to anticancer drugs, especially in HCV-positive HCC patients.
AB - p62/Sqstm1 is a multifunctional protein involved in cell survival, growth and death, that is degraded by autophagy. Amplification of the p62/Sqstm1 gene, and aberrant accumulation and phosphorylation of p62/Sqstm1, have been implicated in tumour development. Herein, we reveal the molecular mechanism of p62/Sqstm1-dependent malignant progression, and suggest that molecular targeting of p62/Sqstm1 represents a potential chemotherapeutic approach against hepatocellular carcinoma (HCC). Phosphorylation of p62/Sqstm1 at Ser349 directs glucose to the glucuronate pathway, and glutamine towards glutathione synthesis through activation of the transcription factor Nrf2. These changes provide HCC cells with tolerance to anti-cancer drugs and proliferation potency. Phosphorylated p62/Sqstm1 accumulates in tumour regions positive for hepatitis C virus (HCV). An inhibitor of phosphorylated p62-dependent Nrf2 activation suppresses the proliferation and anticancer agent tolerance of HCC. Our data indicate that this Nrf2 inhibitor could be used to make cancer cells less resistant to anticancer drugs, especially in HCV-positive HCC patients.
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UR - http://www.scopus.com/inward/citedby.url?scp=84976586533&partnerID=8YFLogxK
U2 - 10.1038/ncomms12030
DO - 10.1038/ncomms12030
M3 - Article
C2 - 27345495
AN - SCOPUS:84976586533
SN - 2041-1723
VL - 7
JO - Nature Communications
JF - Nature Communications
M1 - 12030
ER -
