2021 Vol. 12, No. 3

Paving the way towards cancer: 11q13 amplicon fuels cancer cells with SHANK2 to dislodge HIPPO. Certain oncogenes are amplified in cancer cells to promote tumorigenesis. Xu et al. demonstrated that amongst genes on the 11q13 tumor amplicon, SHANK2 is the most frequently amplified gene in human cancers and acts as an oncogene. SHANK2 is a novel and evlutionarily conserved regulator of HIPPO pathway. Through competitive binding, overexpressed SHANK2 displaces LATS kinase from its activator, thereby librating YAP to promote tumor formation.

Recollection
Professor Cuifen Huang: a great molecular geneticist and the founder of genetic engineering in China
Wei Gong, Leyi Cui, Yike Ying, Yijing Shen, Jiaqi Bao
2021, 12(3): 159-161. doi: 10.1007/s13238-019-0620-5
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Commentary
Tongue as a first-line immune organ?
Jane Y. Wu
2021, 12(3): 162-164. doi: 10.1007/s13238-020-00802-x
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Review
The function and regulation of TET2 in innate immunity and inflammation
Boyi Cong, Qian Zhang, Xuetao Cao
2021, 12(3): 165-173. doi: 10.1007/s13238-020-00796-6
Abstract:
TET2, a member of ten-eleven translocation (TET) family as α-ketoglutarate- and Fe2+-dependent dioxygenase catalyzing the iterative oxidation of 5-methylcytosine (5mC), has been widely recognized to be an important regulator for normal hematopoiesis especially myelopoiesis. Mutation and dysregulation of TET2 contribute to the development of multiple hematological malignancies. Recent studies reveal that TET2 also plays an important role in innate immune homeostasis by promoting DNA demethylation or independent of its enzymatic activity. Here, we focus on the functions of TET2 in the initiation and resolution of inflammation through epigenetic regulation and signaling network. In addition, we highlight regulation of TET2 at various molecular levels as well as the correlated inflammatory diseases, which will provide the insight to intervene in the pathological process caused by TET2 dysregulation.
Research Articles
SHANK2 is a frequently amplified oncogene with evolutionarily conserved roles in regulating Hippo signaling
Liang Xu, Peixue Li, Xue Hao, Yi Lu, Mingxian Liu, Wenqian Song, Lin Shan, Jiao Yu, Hongyu Ding, Shishuang Chen, Ailing Yang, Yi Arial Zeng, Lei Zhang, Hai Jiang
2021, 12(3): 174-193. doi: 10.1007/s13238-020-00742-6
Abstract:
Dysfunction of the Hippo pathway enables cells to evade contact inhibition and provides advantages for cancerous overgrowth. However, for a significant portion of human cancer, how Hippo signaling is perturbed remains unknown. To answer this question, we performed a genome-wide screening for genes that affect the Hippo pathway in Drosophila and cross-referenced the hit genes with human cancer genome. In our screen, Prosap was identified as a novel regulator of the Hippo pathway that potently affects tissue growth. Interestingly, a mammalian homolog of Prosap, SHANK2, is the most frequently amplified gene on 11q13, a major tumor amplicon in human cancer. Gene amplification profile in this 11q13 amplicon clearly indicates selective pressure for SHANK2 amplification. More importantly, across the human cancer genome, SHANK2 is the most frequently amplified gene that is not located within the Myc amplicon. Further studies in multiple human cell lines confirmed that SHANK2 overexpression causes deregulation of Hippo signaling through competitive binding for a LATS1 activator, and as a potential oncogene, SHANK2 promotes cellular transformation and tumor formation in vivo. In cancer cell lines with deregulated Hippo pathway, depletion of SHANK2 restores Hippo signaling and ceases cellular proliferation. Taken together, these results suggest that SHANK2 is an evolutionarily conserved Hippo pathway regulator, commonly amplified in human cancer and potently promotes cancer. Our study for the first time illustrated oncogenic function of SHANK2, one of the most frequently amplified gene in human cancer. Furthermore, given that in normal adult tissues, SHANK2's expression is largely restricted to the nervous system, SHANK2 may represent an interesting target for anticancer therapy.
Therapeutic silencing miR-146b-5p improves cardiac remodeling in a porcine model of myocardial infarction by modulating the wound reparative phenotype
Yiteng Liao, Hao Li, Hao Cao, Yun Dong, Lei Gao, Zhongmin Liu, Junbo Ge, Hongming Zhu
2021, 12(3): 194-212. doi: 10.1007/s13238-020-00750-6
Abstract:
Fibrotic remodeling is an adverse consequence of immune response-driven phenotypic modulation of cardiac cells following myocardial infarction (MI). MicroRNA- 146b (miR-146b) is an active regulator of immunomodulation, but its function in the cardiac inflammatory cascade and its clinical implication in fibrotic remodeling following MI remain largely unknown. Herein, miR-146b- 5p was found to be upregulated in the infarcted myocardium of mice and the serum of myocardial ischemia patients. Gain- and loss-of-function experiments demonstrated that miR-146b-5p was a hypoxia-induced regulator that governed the pro-fibrotic phenotype transition of cardiac cells. Overexpression of miR-146b-5p activated fibroblast proliferation, migration, and fibroblast-to-myofibroblast transition, impaired endothelial cell function and stress survival, and disturbed macrophage paracrine signaling. Interestingly, the opposite effects were observed when miR-146b-5p expression was inhibited. Luciferase assays and rescue studies demonstrated that the miR-146b-5p target genes mediating the above phenotypic modulations included interleukin 1 receptor associated kinase 1 (IRAK1) and carcinoembryonic antigen related cell adhesion molecule 1 (CEACAM1). Local delivery of a miR-146b-5p antagomir significantly reduced fibrosis and cell death, and upregulated capillary and reparative macrophages in the infarcted myocardium to restore cardiac remodeling and function in both mouse and porcine MI models. Local inhibition of miR-146b-5p may represent a novel therapeutic approach to treat cardiac fibrotic remodeling and dysfunction following MI.
Letters
ZFP281 recruits polycomb repressive complex 2 to restrict extraembryonic endoderm potential in safeguarding embryonic stem cell pluripotency
Xin Huang, Nazym Bashkenova, Jihong Yang, Dan Li, Jianlong Wang
2021, 12(3): 213-219. doi: 10.1007/s13238-020-00775-x
Abstract:
Structure of intact human MCU supercomplex with the auxiliary MICU subunits
Wei Zhuo, Heng Zhou, Runyu Guo, Jingbo Yi, Laixing Zhang, Lei Yu, Yinqiang Sui, Wenwen Zeng, Peiyi Wang, Maojun Yang
2021, 12(3): 220-229. doi: 10.1007/s13238-020-00776-w
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Re-detectable positive SARS-CoV-2 RNA tests in patients who recovered from COVID-19 with intestinal infection
Wanyin Tao, Xiaofang Wang, Guorong Zhang, Meng Guo, Huan Ma, Dan Zhao, Yong Sun, Jun He, Lianxin Liu, Kaiguang Zhang, Yucai Wang, Jianping Weng, Xiaoling Ma, Tengchuan Jin, Shu Zhu
2021, 12(3): 230-235. doi: 10.1007/s13238-020-00778-8
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