Subjects: Biology >> Biophysics >> Oncology submitted time 2016-05-12
Huang, Zhaohui
Zhang, Binbin
Quan, Cao
Bian, Zehua
Hua, Dong
Huang, Zhaohui
Cheng, Haipeng
Chen, Xiaoping
Fushimi, Kazuo
Wu, Jane Y.
Wen, Pushuai
Kong, Ruirui
Chen, Mengmeng
Liu, Jianghong
Zhu, Li
Wu, Jane Y.
Zhang, Zhenfeng
Du, Xiang
Abstract： Originally discovered in neuronal guidance, the Slit-Robo pathway is emerging as an important player in human cancers. However, its involvement and mechanism in colorectal cancer (CRC) remains to be elucidated. Here, we report that Slit2 expression is reduced in CRC tissues compared with adjacent noncancerous tissues. Extensive promoter hypermethylation of the Slit2 gene has been observed in CRC cells, which provides a mechanistic explanation for the Slit2 downregulation in CRC. Functional studies showed that Slit2 inhibits CRC cell migration in a Robo-dependent manner. Robo-interacting ubiquitin-specific protease 33 (USP33) is required for the inhibitory function of Slit2 on CRC cell migration by deubiquitinating and stabilizing Robo1. USP33 expression is downregulated in CRC samples, and reduced USP33 mRNA levels are correlated with increased tumor grade, lymph node metastasis and poor patient survival. Taken together, our data reveal USP33 as a previously unknown tumor-suppressing gene for CRC by mediating the inhibitory function of Slit-Robo signaling on CRC cell migration. Our work suggests the potential value of USP33 as an independent prognostic marker of CRC.
Peer Review Status:
Awaiting Review
Subjects: Biology >> Biophysics >> Genetics & Heredity submitted time 2016-05-11
Deng, Jianwen
Yang, Mengxue
Liu, Jianghong
Sun, Shufeng
Zhu, Li
Wu, Jane Y.
Deng, Jianwen
Yang, Mengxue
Yang, Mengxue
Chen, Yanbo
Chen, Xiaoping
Cheng, Haipeng
Li, Yang
Fushimi, Kazuo
Wu, Jane Y.
Chen, Yanbo
Xu, Qi
Chen, Yanbo
Xu, Qi
Li, Yang
Abstract： FUS-proteinopathies, a group of heterogeneous disorders including ALS-FUS and FTLD-FUS, are characterized by the formation of inclusion bodies containing the nuclear protein FUS in the affected patients. However, the underlying molecular and cellular defects remain unclear. Here we provide evidence for mitochondrial localization of FUS and its induction of mitochondrial damage. Remarkably, FTLD-FUS brain samples show increased FUS expression and mitochondrial defects. Biochemical and genetic data demonstrate that FUS interacts with a mitochondrial chaperonin, HSP60, and that FUS translocation to mitochondria is, at least in part, mediated by HSP60. Down-regulating HSP60 reduces mitochondrially localized FUS and partially rescues mitochondrial defects and neurodegenerative phenotypes caused by FUS expression in transgenic flies. This is the first report of direct mitochondrial targeting by a nuclear protein associated with neurodegeneration, suggesting that mitochondrial impairment may represent a critical event in different forms of FUS-proteinopathies and a common pathological feature for both ALS-FUS and FTLD-FUS. Our study offers a potential explanation for the highly heterogeneous nature and complex genetic presentation of different forms of FUS-proteinopathies. Our data also suggest that mitochondrial damage may be a target in future development of diagnostic and therapeutic tools for FUS-proteinopathies, a group of devastating neurodegenerative diseases.
Peer Review Status:Awaiting Review
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