N6-Methyladenosine Reader YTHDF1 Promotes ARHGEF2 Translation and RhoA Signaling in Colorectal Cancer

N6-methyladenosine (m6A) governs the fate of RNAs through m6A readers. Colorectal cancer (CRC) exhibits aberrant m6A modifications and expression of m6A regulators. However, how m6A readers interpret oncogenic m6A methylome to promote malignant transformation remains to be illustrated. YTH N6-methyl...

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Veröffentlicht in:Gastroenterology (New York, N.Y. 1943) N.Y. 1943), 2022-04, Vol.162 (4), p.1183-1196
Hauptverfasser: Wang, Shiyan, Gao, Shanshan, Zeng, Yong, Zhu, Lin, Mo, Yulin, Wong, Chi Chun, Bao, Yi, Su, Peiran, Zhai, Jianning, Wang, Lina, Soares, Fraser, Xu, Xin, Chen, Huarong, Hezaveh, Kebria, Ci, Xinpei, He, Aobo, McGaha, Tracy, O’Brien, Catherine, Rottapel, Robert, Kang, Wei, Wu, Jianfeng, Zheng, Gang, Cai, Zongwei, Yu, Jun, He, Housheng Hansen
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container_end_page 1196
container_issue 4
container_start_page 1183
container_title Gastroenterology (New York, N.Y. 1943)
container_volume 162
creator Wang, Shiyan
Gao, Shanshan
Zeng, Yong
Zhu, Lin
Mo, Yulin
Wong, Chi Chun
Bao, Yi
Su, Peiran
Zhai, Jianning
Wang, Lina
Soares, Fraser
Xu, Xin
Chen, Huarong
Hezaveh, Kebria
Ci, Xinpei
He, Aobo
McGaha, Tracy
O’Brien, Catherine
Rottapel, Robert
Kang, Wei
Wu, Jianfeng
Zheng, Gang
Cai, Zongwei
Yu, Jun
He, Housheng Hansen
description N6-methyladenosine (m6A) governs the fate of RNAs through m6A readers. Colorectal cancer (CRC) exhibits aberrant m6A modifications and expression of m6A regulators. However, how m6A readers interpret oncogenic m6A methylome to promote malignant transformation remains to be illustrated. YTH N6-methyladenosine RNA binding protein 1 (Ythdf1) knockout mouse was generated to determine the effect of Ythdf1 in CRC tumorigenesis in vivo. Multiomic analysis of RNA-sequencing, m6A methylated RNA immunoprecipitation sequencing, YTHDF1 RNA immunoprecipitation sequencing, and proteomics were performed to unravel targets of YTHDF1 in CRC. The therapeutic potential of targeting YTHDF1-m6A-Rho/Rac guanine nucleotide exchange factor 2 (ARHGEF2) was evaluated using small interfering RNA (siRNA) encapsulated by lipid nanoparticles (LNP). DNA copy number gain of YTHDF1 is a frequent event in CRC and contributes to its overexpression. High expression of YTHDF1 is significantly associated with metastatic gene signature in patient tumors. Ythdf1 knockout in mice dampened tumor growth in an inflammatory CRC model. YTHDF1 promotes cell growth in CRC cell lines and primary organoids and lung and liver metastasis in vivo. Integrative multiomics analysis identified RhoA activator ARHGEF2 as a key downstream target of YTHDF1. YTHDF1 binds to m6A sites of ARHGEF2 messenger RNA, resulting in enhanced translation of ARHGEF2. Ectopic expression of ARHGEF2 restored impaired RhoA signaling, cell growth, and metastatic ability both in vitro and in vivo caused by YTHDF1 loss, verifying that ARHGEF2 is a key target of YTHDF1. Finally, ARHGEF2 siRNA delivered by LNP significantly suppressed tumor growth and metastasis in vivo. We identify a novel oncogenic epitranscriptome axis of YTHDF1-m6A-ARHGEF2, which regulates CRC tumorigenesis and metastasis. siRNA-delivering LNP drug validated the therapeutic potential of targeting this axis in CRC. [Display omitted] N6-methyladenosine reader YTHDF1 is amplified and overexpressed in colorectal cancer. YTHDF1-m6A-ARHGEF2 axis contributes to tumorigenesis and metastasis in colorectal cancer and is a potential therapeutic target.
doi_str_mv 10.1053/j.gastro.2021.12.269
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Colorectal cancer (CRC) exhibits aberrant m6A modifications and expression of m6A regulators. However, how m6A readers interpret oncogenic m6A methylome to promote malignant transformation remains to be illustrated. YTH N6-methyladenosine RNA binding protein 1 (Ythdf1) knockout mouse was generated to determine the effect of Ythdf1 in CRC tumorigenesis in vivo. Multiomic analysis of RNA-sequencing, m6A methylated RNA immunoprecipitation sequencing, YTHDF1 RNA immunoprecipitation sequencing, and proteomics were performed to unravel targets of YTHDF1 in CRC. The therapeutic potential of targeting YTHDF1-m6A-Rho/Rac guanine nucleotide exchange factor 2 (ARHGEF2) was evaluated using small interfering RNA (siRNA) encapsulated by lipid nanoparticles (LNP). DNA copy number gain of YTHDF1 is a frequent event in CRC and contributes to its overexpression. High expression of YTHDF1 is significantly associated with metastatic gene signature in patient tumors. Ythdf1 knockout in mice dampened tumor growth in an inflammatory CRC model. YTHDF1 promotes cell growth in CRC cell lines and primary organoids and lung and liver metastasis in vivo. Integrative multiomics analysis identified RhoA activator ARHGEF2 as a key downstream target of YTHDF1. YTHDF1 binds to m6A sites of ARHGEF2 messenger RNA, resulting in enhanced translation of ARHGEF2. Ectopic expression of ARHGEF2 restored impaired RhoA signaling, cell growth, and metastatic ability both in vitro and in vivo caused by YTHDF1 loss, verifying that ARHGEF2 is a key target of YTHDF1. Finally, ARHGEF2 siRNA delivered by LNP significantly suppressed tumor growth and metastasis in vivo. We identify a novel oncogenic epitranscriptome axis of YTHDF1-m6A-ARHGEF2, which regulates CRC tumorigenesis and metastasis. siRNA-delivering LNP drug validated the therapeutic potential of targeting this axis in CRC. [Display omitted] N6-methyladenosine reader YTHDF1 is amplified and overexpressed in colorectal cancer. YTHDF1-m6A-ARHGEF2 axis contributes to tumorigenesis and metastasis in colorectal cancer and is a potential therapeutic target.</description><identifier>ISSN: 0016-5085</identifier><identifier>EISSN: 1528-0012</identifier><identifier>DOI: 10.1053/j.gastro.2021.12.269</identifier><identifier>PMID: 34968454</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Adenosine - analogs &amp; derivatives ; Adenosine - metabolism ; Animals ; ARHGEF2 ; Carcinogenesis - genetics ; Colorectal Cancer ; Colorectal Neoplasms - pathology ; Gene Expression Regulation, Neoplastic ; Humans ; Liposomes ; Mice ; N6-Methyladenosine ; Nanoparticle ; Nanoparticles ; Rho Guanine Nucleotide Exchange Factors - genetics ; Rho Guanine Nucleotide Exchange Factors - metabolism ; rhoA GTP-Binding Protein - genetics ; rhoA GTP-Binding Protein - metabolism ; RNA, Small Interfering ; RNA-Binding Proteins - genetics ; RNA-Binding Proteins - metabolism ; YTHDF1</subject><ispartof>Gastroenterology (New York, N.Y. 1943), 2022-04, Vol.162 (4), p.1183-1196</ispartof><rights>2022 The Authors</rights><rights>Copyright © 2022 The Authors. 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Colorectal cancer (CRC) exhibits aberrant m6A modifications and expression of m6A regulators. However, how m6A readers interpret oncogenic m6A methylome to promote malignant transformation remains to be illustrated. YTH N6-methyladenosine RNA binding protein 1 (Ythdf1) knockout mouse was generated to determine the effect of Ythdf1 in CRC tumorigenesis in vivo. Multiomic analysis of RNA-sequencing, m6A methylated RNA immunoprecipitation sequencing, YTHDF1 RNA immunoprecipitation sequencing, and proteomics were performed to unravel targets of YTHDF1 in CRC. The therapeutic potential of targeting YTHDF1-m6A-Rho/Rac guanine nucleotide exchange factor 2 (ARHGEF2) was evaluated using small interfering RNA (siRNA) encapsulated by lipid nanoparticles (LNP). DNA copy number gain of YTHDF1 is a frequent event in CRC and contributes to its overexpression. High expression of YTHDF1 is significantly associated with metastatic gene signature in patient tumors. Ythdf1 knockout in mice dampened tumor growth in an inflammatory CRC model. YTHDF1 promotes cell growth in CRC cell lines and primary organoids and lung and liver metastasis in vivo. Integrative multiomics analysis identified RhoA activator ARHGEF2 as a key downstream target of YTHDF1. YTHDF1 binds to m6A sites of ARHGEF2 messenger RNA, resulting in enhanced translation of ARHGEF2. Ectopic expression of ARHGEF2 restored impaired RhoA signaling, cell growth, and metastatic ability both in vitro and in vivo caused by YTHDF1 loss, verifying that ARHGEF2 is a key target of YTHDF1. Finally, ARHGEF2 siRNA delivered by LNP significantly suppressed tumor growth and metastasis in vivo. We identify a novel oncogenic epitranscriptome axis of YTHDF1-m6A-ARHGEF2, which regulates CRC tumorigenesis and metastasis. siRNA-delivering LNP drug validated the therapeutic potential of targeting this axis in CRC. [Display omitted] N6-methyladenosine reader YTHDF1 is amplified and overexpressed in colorectal cancer. 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Colorectal cancer (CRC) exhibits aberrant m6A modifications and expression of m6A regulators. However, how m6A readers interpret oncogenic m6A methylome to promote malignant transformation remains to be illustrated. YTH N6-methyladenosine RNA binding protein 1 (Ythdf1) knockout mouse was generated to determine the effect of Ythdf1 in CRC tumorigenesis in vivo. Multiomic analysis of RNA-sequencing, m6A methylated RNA immunoprecipitation sequencing, YTHDF1 RNA immunoprecipitation sequencing, and proteomics were performed to unravel targets of YTHDF1 in CRC. The therapeutic potential of targeting YTHDF1-m6A-Rho/Rac guanine nucleotide exchange factor 2 (ARHGEF2) was evaluated using small interfering RNA (siRNA) encapsulated by lipid nanoparticles (LNP). DNA copy number gain of YTHDF1 is a frequent event in CRC and contributes to its overexpression. High expression of YTHDF1 is significantly associated with metastatic gene signature in patient tumors. Ythdf1 knockout in mice dampened tumor growth in an inflammatory CRC model. YTHDF1 promotes cell growth in CRC cell lines and primary organoids and lung and liver metastasis in vivo. Integrative multiomics analysis identified RhoA activator ARHGEF2 as a key downstream target of YTHDF1. YTHDF1 binds to m6A sites of ARHGEF2 messenger RNA, resulting in enhanced translation of ARHGEF2. Ectopic expression of ARHGEF2 restored impaired RhoA signaling, cell growth, and metastatic ability both in vitro and in vivo caused by YTHDF1 loss, verifying that ARHGEF2 is a key target of YTHDF1. Finally, ARHGEF2 siRNA delivered by LNP significantly suppressed tumor growth and metastasis in vivo. We identify a novel oncogenic epitranscriptome axis of YTHDF1-m6A-ARHGEF2, which regulates CRC tumorigenesis and metastasis. siRNA-delivering LNP drug validated the therapeutic potential of targeting this axis in CRC. [Display omitted] N6-methyladenosine reader YTHDF1 is amplified and overexpressed in colorectal cancer. YTHDF1-m6A-ARHGEF2 axis contributes to tumorigenesis and metastasis in colorectal cancer and is a potential therapeutic target.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>34968454</pmid><doi>10.1053/j.gastro.2021.12.269</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0003-2898-3363</orcidid><oa>free_for_read</oa></addata></record>
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source MEDLINE; Elsevier ScienceDirect Journals; Alma/SFX Local Collection
subjects Adenosine - analogs & derivatives
Adenosine - metabolism
Animals
ARHGEF2
Carcinogenesis - genetics
Colorectal Cancer
Colorectal Neoplasms - pathology
Gene Expression Regulation, Neoplastic
Humans
Liposomes
Mice
N6-Methyladenosine
Nanoparticle
Nanoparticles
Rho Guanine Nucleotide Exchange Factors - genetics
Rho Guanine Nucleotide Exchange Factors - metabolism
rhoA GTP-Binding Protein - genetics
rhoA GTP-Binding Protein - metabolism
RNA, Small Interfering
RNA-Binding Proteins - genetics
RNA-Binding Proteins - metabolism
YTHDF1
title N6-Methyladenosine Reader YTHDF1 Promotes ARHGEF2 Translation and RhoA Signaling in Colorectal Cancer
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