p62/Sqstm1 promotes malignancy of HCV-positive hepatocellular carcinoma through Nrf2-dependent metabolic reprogramming

被引：282

作者：

Saito, Tetsuya ^{[1
,2
]}

Ichimura, Yoshinobu ^{[1
,2
]}

Taguchi, Keiko ^{[3
]}

Suzuki, Takafumi ^{[3
]}

Mizushima, Tsunehiro ^{[4
]}

Takagi, Kenji ^{[4
]}

Hirose, Yuki ^{[5
]}

Nagahashi, Masayuki ^{[5
]}

Iso, Tetsuro ^{[3
]}

Fukutomi, Toshiaki ^{[3
]}

Ohishi, Maki ^{[6
]}

Endo, Keiko ^{[6
]}

Uemura, Takefumi ^{[7
]}

Nishito, Yasumasa ^{[8
]}

Okuda, Shujiro ^{[9
]}

Obata, Miki ^{[1
]}

Kouno, Tsuguka ^{[1
]}

Imamura, Riyo ^{[10
]}

Tada, Yukio ^{[10
]}

Obata, Rika ^{[11
]}

Yasuda, Daisuke ^{[11
]}

Takahashi, Kyoko ^{[11
]}

Fujimura, Tsutomu ^{[12
]}

Pi, Jingbo ^{[13
]}

Lee, Myung-Shik ^{[14
,15
]}

Ueno, Takashi ^{[12
]}

Ohe, Tomoyuki ^{[11
]}

Mashino, Tadahiko ^{[11
]}

Wakai, Toshifumi ^{[5
]}

Kojima, Hirotatsu ^{[10
]}

Okabe, Takayoshi ^{[10
]}

Nagano, Tetsuo ^{[10
]}

Motohashi, Hozumi ^{[16
]}

Waguri, Satoshi ^{[7
]}

Soga, Tomoyoshi ^{[6
]}

Yamamoto, Masayuki ^{[3
]}

Tanaka, Keiji ^{[2
]}

Komatsu, Masaaki ^{[1
]}

机构：

[1] Niigata Univ, Grad Sch Med & Dent Sci, Dept Biochem, Niigata 9518510, Japan

[2] Tokyo Metropolitan Inst Med Sci, Lab Prot Metab, Tokyo 1568506, Japan

[3] Tohoku Univ, Dept Med Biochem, Grad Sch Med, Sendai, Miyagi 9808575, Japan

[4] Univ Hyogo, Picobiol Inst, Grad Sch Life Sci, Dept Life Sci, Kobe, Hyogo 6781297, Japan

[5] Niigata Univ, Div Digest & Gen Surg, Grad Sch Med & Dent Sci, Niigata 9518510, Japan

[6] Keio Univ, Inst Adv Biosci, Tsuruoka, Yamagata 9970052, Japan

[7] Fukushima Med Univ, Dept Anat & Histol, Sch Med, Fukushima 9601295, Japan

[8] Tokyo Metropolitan Inst Med Sci, Core Technol & Res Ctr, Tokyo 1568506, Japan

[9] Niigata Univ, Grad Sch Med & Dent Sci, Bioinformat Lab, Niigata 9518510, Japan

[10] Univ Tokyo, Drug Discovery Initiat, Tokyo 1130033, Japan

[11] Keio Univ, Dept Pharmaceut Sci, Fac Pharm, Tokyo 1058512, Japan

[12] Juntendo Univ, Grad Sch Med, Res Support Ctr, Lab Prote & Biomol Sci, Tokyo 1138421, Japan

[13] Hamner Inst Hlth Sci, Inst Chem Safety Sci, Res Triangle Pk, NC 27709 USA

[14] Yonsei Univ, Coll Med, Severance Biomed Sci Inst, Seoul 120752, South Korea

[15] Yonsei Univ, Coll Med, Dept Internal Med, Seoul 120752, South Korea

[16] Tohoku Univ, Inst Dev Aging & Canc, Dept Gene Express Regulat, Sendai, Miyagi 9808575, Japan

来源：

NATURE COMMUNICATIONS | 2016年 / 7卷

关键词：

TRANSCRIPTION FACTOR NRF2; HEPATITIS-C VIRUS; KEAP1-NRF2; PATHWAY; MOLECULAR-BASIS; AUTOPHAGY; P62; DEFICIENCY; MICE; ACTIVATION; ACID;

D O I：

10.1038/ncomms12030

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：16

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