Autophagy activation is required for N6-methyladenosine modification to regulate ferroptosis in hepatocellular carcinoma

被引:27
作者
Li, Yujia [1 ]
Guo, Mei [2 ]
Qiu, Yangling [1 ]
Li, Mengran [1 ]
Wu, Yang [3 ]
Shen, Min [4 ]
Wang, Yingqian [1 ]
Zhang, Feng [1 ]
Shao, Jiangjuan [1 ]
Xu, Xuefen [5 ,6 ]
Zhang, Zili [1 ,7 ]
Zheng, Shizhong [1 ,7 ]
机构
[1] Nanjing Univ Chinese Med, Jiangsu Key Lab Pharmacol & Safety Evaluat Chinese, Nanjing 210023, Peoples R China
[2] Nanjing Univ Chinese Med, Sch Nursing, Nanjing 210023, Peoples R China
[3] Nanjing Med Univ, Pancreas Ctr, Affiliated Hosp 1, Nanjing 210023, Peoples R China
[4] Yangzhou Univ, Med Coll, Dept Biochem & Mol Biol, Yangzhou 225009, Peoples R China
[5] Nanjing Univ Chinese Med, Sch Med & Holist Integrat Med, Dept Pharmacol, Nanjing, Peoples R China
[6] Nanjing Univ Chinese Med, Sch Med & Holist Integrat Med, Dept Pharmacol, 138 Xianlin Ave, Nanjing 210023, Jiangsu, Peoples R China
[7] Nanjing Univ Chinese Med, Sch Pharmacol, 138 Xianlin Ave, Nanjing 210023, Jiangsu, Peoples R China
来源
REDOX BIOLOGY | 2024年 / 69卷
基金
中国国家自然科学基金;
关键词
Autophagy; Translation; Ferroptosis; Hepatocellular carcinoma; m; 6; A; RNA; RESISTANCE; TARGETS;
D O I
10.1016/j.redox.2023.102971
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Background & aims: Although ferroptosis holds promise as a new strategy for treating hepatocellular carcinoma (HCC), there are several obstacles that need to be overcome. One major challenge is the lack of understanding about the mechanisms underlying ferroptosis. Additionally, while the m6A modification has been shown to regulate various forms of cell death, its role in regulating ferroptosis in HCC has been largely overlooked. Bridging this knowledge gap, our study aimed to elucidate the regulatory influence of m6A modification on HCC ferroptosis. Materials: Dot blot and EpiQuik m6A RNA Methylation Quantitative kit detected changes in overall m6A modification level during ferroptosis in HCC. MeRIP-qPCR and RIP-qPCR identified that the m6A modification of ATG5 mRNA was significant changed. BALB/c nude mice were used to construct xenograft tumor models to verify the phenotypes upon YTHDC2 silencing. In addition, patient-derived organoid models were used to demonstrate that induction of ferroptosis was an effective strategy against HCC. Results: Our study has shown that inducing ferroptosis is a promising strategy for combatting HCC. Specifically, we have found a significant correlation between ferroptosis and high levels of m6A modification in HCC. Notably, we discovered that the elevation of ATG5 mRNA m6A modification mediated by WTAP is dependent on the reading protein YTHDC2. Importantly, inhibition of either WTAP or YTHDC2 effectively prevented ferroptosis and suppressed HCC development in both in vitro and in vivo models. Conclusion: Our study revealed that WTAP upregulates ATG5 expression post-transcriptionally in an m6AYTHDC2-dependent manner, thereby promoting the translation of ATG5 mRNA during ferroptosis in HCC. These findings have significant implications for the development of innovative and effective therapeutic approaches for HCC treatment.
引用
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页数:15
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共 43 条
  • [1] Ferroptosis in Hepatocellular Carcinoma: Mechanisms, Drug Targets and Approaches to Clinical Translation
    Bekric, Dino
    Ocker, Matthias
    Mayr, Christian
    Stintzing, Sebastian
    Ritter, Markus
    Kiesslich, Tobias
    Neureiter, Daniel
    [J]. CANCERS, 2022, 14 (07)
  • [2] RNA N6-methyladenosine methyltransferase-like 3 promotes liver cancer progression through YTHDF2-dependent posttranscriptional silencing of SOCS2
    Chen, Mengnuo
    Wei, Lai
    Law, Cheuk-Ting
    Tsang, Felice Ho-Ching
    Shen, Jialing
    Cheng, Carol Lai-Hung
    Tsang, Long-Hin
    Ho, Daniel Wai-Hung
    Chiu, David Kung-Chun
    Lee, Joyce Man-Fong
    Wong, Carmen Chak-Lui
    Ng, Irene Oi-Lin
    Wong, Chun-Ming
    [J]. HEPATOLOGY, 2018, 67 (06) : 2254 - 2270
  • [3] The role of m6A RNA methylation in human cancer
    Chen, Xiao-Yu
    Zhang, Jing
    Zhu, Jin-Shui
    [J]. MOLECULAR CANCER, 2019, 18 (1)
  • [4] Cellular degradation systems in ferroptosis
    Chen, Xin
    Yu, Chunhua
    Kang, Rui
    Kroemer, Guido
    Tang, Daolin
    [J]. CELL DEATH AND DIFFERENTIATION, 2021, 28 (04) : 1135 - 1148
  • [5] Ketoconazole exacerbates mitophagy to induce apoptosis by downregulating cyclooxygenase-2 in hepatocellular carcinoma
    Chen, Yan
    Chen, Hai-Ning
    Wang, Kui
    Zhang, Lu
    Huang, Zhao
    Liu, Jiayang
    Zhang, Zhe
    Luo, Maochao
    Lei, Yunlong
    Peng, Yong
    Zhou, Zong-Guang
    Wei, Yuquan
    Huang, Canhua
    [J]. JOURNAL OF HEPATOLOGY, 2019, 70 (01) : 66 - 77
  • [6] CRISPR screens uncover protective effect of PSTK as a regulator of chemotherapy-induced ferroptosis in hepatocellular carcinoma
    Chen, Yiran
    Li, Li
    Lan, Jie
    Cui, Yang
    Rao, Xiaosong
    Zhao, Jing
    Xing, Tao
    Ju, Gaoda
    Song, Guangtao
    Lou, Jizhong
    Liang, Jun
    [J]. MOLECULAR CANCER, 2022, 21 (01)
  • [7] Modeling Development and Disease with Organoids
    Clevers, Hans
    [J]. CELL, 2016, 165 (07) : 1586 - 1597
  • [8] Metabolic dysregulation and emerging therapeutical targets for hepatocellular carcinoma
    Du, Danyu
    Liu, Chan
    Qin, Mengyao
    Zhang, Xiao
    Xi, Tao
    Yuan, Shengtao
    Hao, Haiping
    Xiong, Jing
    [J]. ACTA PHARMACEUTICA SINICA B, 2022, 12 (02) : 558 - 580
  • [9] Functions of N6-methyladenosine and its role in cancer
    He, Liuer
    Li, Huiyu
    Wu, Anqi
    Peng, Yulong
    Shu, Guang
    Yin, Gang
    [J]. MOLECULAR CANCER, 2019, 18 (01)
  • [10] Autophagy promotes ferroptosis by degradation of ferritin
    Hou, Wen
    Xie, Yangchun
    Song, Xinxin
    Sun, Xiaofang
    Lotze, Michael T.
    Zeh, Herbert J.
    Kang, Rui
    Tang, Daolin
    [J]. AUTOPHAGY, 2016, 12 (08) : 1425 - 1428