Oct 2021, Volume 12 Issue 10

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    Wei Gong, Yijing Shen, Jiaqi Bao, Yike Ying, Han Zhou, Zhifeng Wu
    Fang Li, Meng Luo, Wenyang Zhou, Jinliang Li, Xiyun Jin, Zhaochun Xu, Liran Juan, Zheng Zhang, Yuou Li, Renqiang Liu, Yiqun Li, Chang Xu, Kexin Ma, Huimin Cao, Jingwei Wang, Pingping Wang, Zhigao Bu, Qinghua Jiang
    Xuwen Li, Zijian Zhang, Xinlong Luo, Jacob Schrier, Andrew D. Yang, Tao P. Wu

    N6-methyladenine (N6-mA, m6dA, or 6mA), a prevalent DNA modification in prokaryotes, has recently been identified in higher eukaryotes, including mammals. Although 6mA has been well-studied in prokaryotes, the function and regulatory mechanism of 6mA in eukaryotes are still poorly understood. Recent studies indicate that 6mA can serve as an epigenetic mark and play critical roles in various biological processes, from transposable-element suppression to environmental stress response. Here, we review the significant advances in methodology for 6mA detection and major progress in understanding the regulation and function of this non-canonical DNA methylation in eukaryotes, predominantly mammals.

    Xiaoyan Xu, Yaqin Sun, Xufeng Cen, Bing Shan, Qingwei Zhao, Tingxue Xie, Zhe Wang, Tingjun Hou, Yu Xue, Mengmeng Zhang, Di Peng, Qiming Sun, Cong Yi, Ayaz Najafov, Hongguang Xia

    Chaperone-mediated autophagy (CMA) is a lysosomedependent selective degradation pathway implicated in the pathogenesis of cancer and neurodegenerative diseases. However, the mechanisms that regulate CMA are not fully understood. Here, using unbiased drug screening approaches, we discover Metformin, a drug that is commonly the first medication prescribed for type 2 diabetes, can induce CMA. We delineate the mechanism of CMA induction by Metformin to be via activation of TAK1-IKKα/β signaling that leads to phosphorylation of Ser85 of the key mediator of CMA, Hsc70, and its activation. Notably, we find that amyloid-beta precursor protein (APP) is a CMA substrate and that it binds to Hsc70 in an IKKα/β-dependent manner. The inhibition of CMA-mediated degradation of APP enhances its cytotoxicity. Importantly, we find that in the APP/ PS1 mouse model of Alzheimer’s disease (AD), activation of CMA by Hsc70 overexpression or Metformin potently reduces the accumulated brain Aβ plaque levels and reverses the molecular and behavioral AD phenotypes. Our study elucidates a novel mechanism of CMA regulation via Metformin-TAK1-IKKα/β-Hsc70 signaling and suggests Metformin as a new activator of CMA for diseases, such as AD, where such therapeutic intervention could be beneficial.

    Shi Wei, Miaomiao Dai, Chi Zhang, Kai Teng, Fengwei Wang, Hongbo Li, Weipeng Sun, Zihao Feng, Tiebang Kang, Xinyuan Guan, Ruihua Xu, Muyan Cai, Dan Xie

    Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is the fourth-leading cause of cancer-related deaths worldwide. HCC is refractory to many standard cancer treatments and the prognosis is often poor, highlighting a pressing need to identify biomarkers of aggressiveness and potential targets for future treatments. Kinesin family member 2C (KIF2C) is reported to be highly expressed in several human tumors. Nevertheless, the molecular mechanisms underlying the role of KIF2C in tumor development and progression have not been investigated. In this study, we found that KIF2C expression was significantly upregulated in HCC, and that KIF2C up-regulation was associated with a poor prognosis. Utilizing both gain and loss of function assays, we showed that KIF2C promoted HCC cell proliferation, migration, invasion, and metastasis both in vitro and in vivo. Mechanistically, we identified TBC1D7 as a binding partner of KIF2C, and this interaction disrupts the formation of the TSC complex, resulting in the enhancement of mammalian target of rapamycin complex1 (mTORC1) signal transduction. Additionally, we found that KIF2C is a direct target of the Wnt/β-catenin pathway, and acts as a key factor in mediating the crosstalk between Wnt/β-catenin and mTORC1 signaling. Thus, the results of our study establish a link between Wnt/β-catenin and mTORC1 signaling, which highlights the potential of KIF2C as a therapeutic target for the treatment of HCC.

    Yongcun Qu, Qi Chen, Shanshan Guo, Chiyuan Ma, Yonggang Lu, Junchao Shi, Shichao Liu, Tong Zhou, Taichi Noda, Jingjing Qian, Liwen Zhang, Xili Zhu, Xiaohua Lei, Yujing Cao, Wei Li, Wei Li, Nicolas Plachta, Martin M. Matzuk, Masahito Ikawa, Enkui Duan, Ying Zhang, Hongmei Wang
    Xingdong Zhou, Hui Wang, Qun Ji, Mingjuan Du, Yuexia Liang, Huanhuan Li, Fan Li, Hang Shang, Xiujuan Zhu, Wei Wang, Lichun Jiang, Alexey V. Stepanov, Tianyu Ma, Nanxin Gong, Xiaodong Jia, Alexander G. Gabibov, Zhiyong Lou, Yinying Lu, Yu Guo, Hongkai Zhang, Xiaoming Yang