Alternative splicing perturbation landscape identifies RNA binding proteins as potential therapeutic targets in cancer

Alternative splicing (AS) plays an important role in gene regulation, and AS perturbations are frequently observed in cancer. RNA binding protein (RBP) is one of the molecular determinants of AS, and perturbations in RBP-gene network activity are causally associated with cancer development. Here, we...

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Main Authors:	Junyi Li, Tao Pan, Liuxin Chen, Qi Wang, Zhenghong Chang, Weiwei Zhou, Xinhui Li, Gang Xu, Xia Li, Yongsheng Li, Yunpeng Zhang
Format:	Article
Language:	English
Published:	Elsevier 2021-06-01
Series:	Molecular Therapy: Nucleic Acids
Subjects:	RNA binding protein alterative splicing regulatory network cancer therapeutic targets
Online Access:	http://www.sciencedirect.com/science/article/pii/S2162253121000998

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spelling	doaj-b1d1b3f7f2854d0392fc3347f9f2c2ef2021-06-05T06:08:27ZengElsevierMolecular Therapy: Nucleic Acids2162-25312021-06-0124792806Alternative splicing perturbation landscape identifies RNA binding proteins as potential therapeutic targets in cancerJunyi Li0Tao Pan1Liuxin Chen2Qi Wang3Zhenghong Chang4Weiwei Zhou5Xinhui Li6Gang Xu7Xia Li8Yongsheng Li9Yunpeng Zhang10College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, ChinaKey Laboratory of Tropical Translational Medicine of Ministry of Education, College of Biomedical Information and Engineering, Hainan Medical University, Haikou 571199, ChinaCollege of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, ChinaCollege of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, ChinaCollege of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, ChinaCollege of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, ChinaCollege of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, ChinaKey Laboratory of Tropical Translational Medicine of Ministry of Education, College of Biomedical Information and Engineering, Hainan Medical University, Haikou 571199, ChinaCollege of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China; Key Laboratory of Tropical Translational Medicine of Ministry of Education, College of Biomedical Information and Engineering, Hainan Medical University, Haikou 571199, China; Corresponding author: Xia Li, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China.Key Laboratory of Tropical Translational Medicine of Ministry of Education, College of Biomedical Information and Engineering, Hainan Medical University, Haikou 571199, China; Corresponding author: Yongsheng Li, Key Laboratory of Tropical Translational Medicine of Ministry of Education, College of Biomedical Information and Engineering, Hainan Medical University, Haikou 571199, China.College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China; Key Laboratory of Tropical Translational Medicine of Ministry of Education, College of Biomedical Information and Engineering, Hainan Medical University, Haikou 571199, China; Corresponding author: Yunpeng Zhang, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China.Alternative splicing (AS) plays an important role in gene regulation, and AS perturbations are frequently observed in cancer. RNA binding protein (RBP) is one of the molecular determinants of AS, and perturbations in RBP-gene network activity are causally associated with cancer development. Here, we performed a systematic analysis to characterize the perturbations in AS events across 18 cancer types. We showed that AS alterations were prevalent in cancer and involved in cancer-related pathways. Given that the extent of AS perturbation was associated with disease severity, we proposed a computational pipeline to identify RBP regulators. Pan-cancer analysis identified a number of conserved RBP regulators, which play important roles in regulating AS of genes involved in cancer hallmark pathways. Our application analysis revealed that the expression of 68 RBP regulators helped in cancer subtyping. Specifically, we identified four subtypes of kidney cancer with differences in cancer hallmark pathway activities and prognosis. Finally, we identified the small molecules that can potentially target the RBP genes and suggested potential candidates for cancer therapy. In summary, our comprehensive AS perturbation landscape analysis identified RBPs as potential therapeutic targets in cancer and provided novel insights into the regulatory functions of RBPs in cancer.http://www.sciencedirect.com/science/article/pii/S2162253121000998RNA binding proteinalterative splicingregulatory networkcancertherapeutic targets
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Junyi Li Tao Pan Liuxin Chen Qi Wang Zhenghong Chang Weiwei Zhou Xinhui Li Gang Xu Xia Li Yongsheng Li Yunpeng Zhang
spellingShingle	Junyi Li Tao Pan Liuxin Chen Qi Wang Zhenghong Chang Weiwei Zhou Xinhui Li Gang Xu Xia Li Yongsheng Li Yunpeng Zhang Alternative splicing perturbation landscape identifies RNA binding proteins as potential therapeutic targets in cancer Molecular Therapy: Nucleic Acids RNA binding protein alterative splicing regulatory network cancer therapeutic targets
author_facet	Junyi Li Tao Pan Liuxin Chen Qi Wang Zhenghong Chang Weiwei Zhou Xinhui Li Gang Xu Xia Li Yongsheng Li Yunpeng Zhang
author_sort	Junyi Li
title	Alternative splicing perturbation landscape identifies RNA binding proteins as potential therapeutic targets in cancer
title_short	Alternative splicing perturbation landscape identifies RNA binding proteins as potential therapeutic targets in cancer
title_full	Alternative splicing perturbation landscape identifies RNA binding proteins as potential therapeutic targets in cancer
title_fullStr	Alternative splicing perturbation landscape identifies RNA binding proteins as potential therapeutic targets in cancer
title_full_unstemmed	Alternative splicing perturbation landscape identifies RNA binding proteins as potential therapeutic targets in cancer
title_sort	alternative splicing perturbation landscape identifies rna binding proteins as potential therapeutic targets in cancer
publisher	Elsevier
series	Molecular Therapy: Nucleic Acids
issn	2162-2531
publishDate	2021-06-01
description	Alternative splicing (AS) plays an important role in gene regulation, and AS perturbations are frequently observed in cancer. RNA binding protein (RBP) is one of the molecular determinants of AS, and perturbations in RBP-gene network activity are causally associated with cancer development. Here, we performed a systematic analysis to characterize the perturbations in AS events across 18 cancer types. We showed that AS alterations were prevalent in cancer and involved in cancer-related pathways. Given that the extent of AS perturbation was associated with disease severity, we proposed a computational pipeline to identify RBP regulators. Pan-cancer analysis identified a number of conserved RBP regulators, which play important roles in regulating AS of genes involved in cancer hallmark pathways. Our application analysis revealed that the expression of 68 RBP regulators helped in cancer subtyping. Specifically, we identified four subtypes of kidney cancer with differences in cancer hallmark pathway activities and prognosis. Finally, we identified the small molecules that can potentially target the RBP genes and suggested potential candidates for cancer therapy. In summary, our comprehensive AS perturbation landscape analysis identified RBPs as potential therapeutic targets in cancer and provided novel insights into the regulatory functions of RBPs in cancer.
topic	RNA binding protein alterative splicing regulatory network cancer therapeutic targets
url	http://www.sciencedirect.com/science/article/pii/S2162253121000998
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Alternative splicing perturbation landscape identifies RNA binding proteins as potential therapeutic targets in cancer

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