The Long Noncoding RNA CCAT2 Induces Chromosomal Instability
Through BOP1-AURKB Signaling

J 2020

The Long Noncoding RNA CCAT2 Induces Chromosomal Instability Through BOP1-AURKB Signaling

CHEN, B. Q., M. P. DRAGOMIR, L. FABRIS, R. BAYRAKTAR, E. KNUTSEN et. al.

Basic information

Original name

The Long Noncoding RNA CCAT2 Induces Chromosomal Instability Through BOP1-AURKB Signaling

Authors

CHEN, B. Q., M. P. DRAGOMIR, L. FABRIS, R. BAYRAKTAR, E. KNUTSEN, X. LIU, C. Y. TANG, Y. F. LI, T. SHIMURA, Tina CATELA IVKOVIĆ (191 Croatia, belonging to the institution), M. C. DE LOS SANTOS, S. ANFOSSI, M. SHIMIZU, M. Y. SHAH, H. LING, P. SHEN, A. S. MULTANI, B. PARDINI, J. K. BURKS, H.. KATAYAMA, L. C. REINEKE, L. F. HUO, M. SYED, S. M. SONG, M. FERRACIN, E. OKI, B. FROMM, C. IVAN, K. BHUVANESHWAR, Y. GUSEV, K. MIMORI, D. MENTER, S. SEN, T. MATSUYAMA, H. UETAKE, C. VASILESCU, S. KOPETZ, J. PARKER-THORNBURG, A. TAGUCHI (guarantor), S. M. HANASH, L. GIRNITA, Ondřej SLABÝ (203 Czech Republic, belonging to the institution), A. GOEL, G. VARANI, M. GAGEA, C. L. LI, J. A. AJANI and G. A. CALIN

Edition

Gastroenterology, Philadelphia, W B Saunders co-Elsevier Inc, 2020, 0016-5085

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30219 Gastroenterology and hepatology

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 22.682

RIV identification code

RIV/00216224:14740/20:00118277

Organization unit

Central European Institute of Technology

DOI

http://dx.doi.org/10.1053/j.gastro.2020.08.018

UT WoS

000597825700001

Keywords in English

MSS; Aneuploidy; Tumorigenesis; Noncoding RNA

Abstract

V originále

BACKGROUND & AIMS: Chromosomal instability (CIN) is a carcinogenesis event that promotes metastasis and resistance to therapy by unclear mechanisms. Expression of the colon cancer-associated transcript 2 gene (CCAT2), which encodes a long noncoding RNA (lncRNA), associates with CIN, but little is known about how CCAT2 lncRNA regulates this cancer enabling characteristic. METHODS: We performed cytogenetic analysis of colorectal cancer (CRC) cell lines (HCT116, KM12C/SM, and HT29) overexpressing CCAT2 and colon organoids from C57BL/6N mice with the CCAT2 transgene and without (controls). CRC cells were also analyzed by immunofluorescence microscopy, g-H2AX, and senescence assays. CCAT2 transgene and control mice were given azoxymethane and dextran sulfate sodium to induce colon tumors. We performed gene expression array and mass spectrometry to detect downstream targets of CCAT2 lncRNA. We characterized interactions between CCAT2 with downstream proteins using MS2 pull-down, RNA immunoprecipitation, and selective 20-hydroxyl acylation analyzed by primer extension analyses. Downstream proteins were overexpressed in CRC cells and analyzed for CIN. Gene expression levels were measured in CRC and non-tumor tissues from 5 cohorts, comprising more than 900 patients. RESULTS: High expression of CCAT2 induced CIN in CRC cell lines and increased resistance to 5-fluorouracil and oxaliplatin. Mice that expressed the CCAT2 transgene developed chromosome abnormalities, and colon organoids derived from crypt cells of these mice had a higher percentage of chromosome abnormalities compared with organoids from control mice. The transgenic mice given azoxymethane and dextran sulfate sodium developed more and larger colon polyps than control mice given these agents. Microarray analysis and mass spectrometry indicated that expression of CCAT2 increased expression of genes involved in ribosome biogenesis and protein synthesis. CCAT2 lncRNA interacted directly with and stabilized BOP1 ribosomal biogenesis factor (BOP1). CCAT2 also increased expression of MYC, which activated expression of BOP1. Overexpression of BOP1 in CRC cell lines resulted in chromosomal missegregation errors, and increased colony formation, and invasiveness, whereas BOP1 knockdown reduced viability. BOP1 promoted CIN by increasing the active form of aurora kinase B, which regulates chromosomal segregation. BOP1 was overexpressed in polyp tissues from CCAT2 transgenic mice compared with healthy tissue. CCAT2 lncRNA and BOP1 mRNA or protein were all increased in micro satellite stable tumors (characterized by CIN), but not in tumors with microsatellite instability compared with nontumor tissues. Increased levels of CCAT2 lncRNA and BOP1 mRNA correlated with each other and with shorter survival times of patients. CONCLUSIONS: We found that overexpression of CCAT2 in colon cells promotes CIN and carcinogenesis by stabilizing and inducing expression of BOP1 an activator of aurora kinase B. Strategies to target this pathway might be developed for treatment of patients with microsatellite stable colorectal tumors.

Citovat

CHEN, B. Q., M. P. DRAGOMIR, L. FABRIS, R. BAYRAKTAR, E. KNUTSEN, X. LIU, C. Y. TANG, Y. F. LI, T. SHIMURA, Tina CATELA IVKOVIĆ, M. C. DE LOS SANTOS, S. ANFOSSI, M. SHIMIZU, M. Y. SHAH, H. LING, P. SHEN, A. S. MULTANI, B. PARDINI, J. K. BURKS, H.. KATAYAMA, L. C. REINEKE, L. F. HUO, M. SYED, S. M. SONG, M. FERRACIN, E. OKI, B. FROMM, C. IVAN, K. BHUVANESHWAR, Y. GUSEV, K. MIMORI, D. MENTER, S. SEN, T. MATSUYAMA, H. UETAKE, C. VASILESCU, S. KOPETZ, J. PARKER-THORNBURG, A. TAGUCHI, S. M. HANASH, L. GIRNITA, Ondřej SLABÝ, A. GOEL, G. VARANI, M. GAGEA, C. L. LI, J. A. AJANI and G. A. CALIN. The Long Noncoding RNA CCAT2 Induces Chromosomal Instability Through BOP1-AURKB Signaling. Gastroenterology. Philadelphia: W B Saunders co-Elsevier Inc, 2020, vol. 159, No 6, p. 2146-2195. ISSN 0016-5085. Available from: https://dx.doi.org/10.1053/j.gastro.2020.08.018.

@article{1746828,
   author = {Chen, B. Q. and Dragomir, M. P. and Fabris, L. and Bayraktar, R. and Knutsen, E. and Liu, X. and Tang, C. Y. and Li, Y. F. and Shimura, T. and Catela Ivković, Tina and De los Santos, M. C. and Anfossi, S. and Shimizu, M. and Shah, M. Y. and Ling, H. and Shen, P. and Multani, A. S. and Pardini, B. and Burks, J. K. and Katayama, H.. and Reineke, L. C. and Huo, L. F. and Syed, M. and Song, S. M. and Ferracin, M. and Oki, E. and Fromm, B. and Ivan, C. and Bhuvaneshwar, K. and Gusev, Y. and Mimori, K. and Menter, D. and Sen, S. and Matsuyama, T. and Uetake, H. and Vasilescu, C. and Kopetz, S. and ParkerandThornburg, J. and Taguchi, A. and Hanash, S. M. and Girnita, L. and Slabý, Ondřej and Goel, A. and Varani, G. and Gagea, M. and Li, C. L. and Ajani, J. A. and Calin, G. A.},
   article_location = {Philadelphia},
   article_number = {6},
   doi = {http://dx.doi.org/10.1053/j.gastro.2020.08.018},
   keywords = {MSS; Aneuploidy; Tumorigenesis; Noncoding RNA},
   language = {eng},
   issn = {0016-5085},
   journal = {Gastroenterology},
   title = {The Long Noncoding RNA CCAT2 Induces Chromosomal Instability Through BOP1-AURKB Signaling},
   url = {https://www.sciencedirect.com/science/article/abs/pii/S0016508520350575?via%3Dihub},
   volume = {159},
   year = {2020}
}

TY  - JOUR
ID  - 1746828
AU  - Chen, B. Q. - Dragomir, M. P. - Fabris, L. - Bayraktar, R. - Knutsen, E. - Liu, X. - Tang, C. Y. - Li, Y. F. - Shimura, T. - Catela Ivković, Tina - De los Santos, M. C. - Anfossi, S. - Shimizu, M. - Shah, M. Y. - Ling, H. - Shen, P. - Multani, A. S. - Pardini, B. - Burks, J. K. - Katayama, H.. - Reineke, L. C. - Huo, L. F. - Syed, M. - Song, S. M. - Ferracin, M. - Oki, E. - Fromm, B. - Ivan, C. - Bhuvaneshwar, K. - Gusev, Y. - Mimori, K. - Menter, D. - Sen, S. - Matsuyama, T. - Uetake, H. - Vasilescu, C. - Kopetz, S. - Parker-Thornburg, J. - Taguchi, A. - Hanash, S. M. - Girnita, L. - Slabý, Ondřej - Goel, A. - Varani, G. - Gagea, M. - Li, C. L. - Ajani, J. A. - Calin, G. A.
PY  - 2020
TI  - The Long Noncoding RNA CCAT2 Induces Chromosomal Instability Through BOP1-AURKB Signaling
JF  - Gastroenterology
VL  - 159
IS  - 6
SP  - 2146-2195
EP  - 2146-2195
PB  - W B Saunders co-Elsevier Inc
SN  - 00165085
KW  - MSS
KW  - Aneuploidy
KW  - Tumorigenesis
KW  - Noncoding RNA
UR  - https://www.sciencedirect.com/science/article/abs/pii/S0016508520350575?via%3Dihub
N2  - BACKGROUND & AIMS: Chromosomal instability (CIN) is a carcinogenesis event that promotes metastasis and resistance to therapy by unclear mechanisms. Expression of the colon cancer-associated transcript 2 gene (CCAT2), which encodes a long noncoding RNA (lncRNA), associates with CIN, but little is known about how CCAT2 lncRNA regulates this cancer enabling characteristic. METHODS: We performed cytogenetic analysis of colorectal cancer (CRC) cell lines (HCT116, KM12C/SM, and HT29) overexpressing CCAT2 and colon organoids from C57BL/6N mice with the CCAT2 transgene and without (controls). CRC cells were also analyzed by immunofluorescence microscopy, g-H2AX, and senescence assays. CCAT2 transgene and control mice were given azoxymethane and dextran sulfate sodium to induce colon tumors. We performed gene expression array and mass spectrometry to detect downstream targets of CCAT2 lncRNA. We characterized interactions between CCAT2 with downstream proteins using MS2 pull-down, RNA immunoprecipitation, and selective 20-hydroxyl acylation analyzed by primer extension analyses. Downstream proteins were overexpressed in CRC cells and analyzed for CIN. Gene expression levels were measured in CRC and non-tumor tissues from 5 cohorts, comprising more than 900 patients. RESULTS: High expression of CCAT2 induced CIN in CRC cell lines and increased resistance to 5-fluorouracil and oxaliplatin. Mice that expressed the CCAT2 transgene developed chromosome abnormalities, and colon organoids derived from crypt cells of these mice had a higher percentage of chromosome abnormalities compared with organoids from control mice. The transgenic mice given azoxymethane and dextran sulfate sodium developed more and larger colon polyps than control mice given these agents. Microarray analysis and mass spectrometry indicated that expression of CCAT2 increased expression of genes involved in ribosome biogenesis and protein synthesis. CCAT2 lncRNA interacted directly with and stabilized BOP1 ribosomal biogenesis factor (BOP1). CCAT2 also increased expression of MYC, which activated expression of BOP1. Overexpression of BOP1 in CRC cell lines resulted in chromosomal missegregation errors, and increased colony formation, and invasiveness, whereas BOP1 knockdown reduced viability. BOP1 promoted CIN by increasing the active form of aurora kinase B, which regulates chromosomal segregation. BOP1 was overexpressed in polyp tissues from CCAT2 transgenic mice compared with healthy tissue. CCAT2 lncRNA and BOP1 mRNA or protein were all increased in micro satellite stable tumors (characterized by CIN), but not in tumors with microsatellite instability compared with nontumor tissues. Increased levels of CCAT2 lncRNA and BOP1 mRNA correlated with each other and with shorter survival times of patients. CONCLUSIONS: We found that overexpression of CCAT2 in colon cells promotes CIN and carcinogenesis by stabilizing and inducing expression of BOP1 an activator of aurora kinase B. Strategies to target this pathway might be developed for treatment of patients with microsatellite stable colorectal tumors.
ER  -

CHEN, B. Q., M. P. DRAGOMIR, L. FABRIS, R. BAYRAKTAR, E. KNUTSEN, X. LIU, C. Y. TANG, Y. F. LI, T. SHIMURA, Tina CATELA IVKOVI$\backslash$'C, M. C. DE LOS SANTOS, S. ANFOSSI, M. SHIMIZU, M. Y. SHAH, H. LING, P. SHEN, A. S. MULTANI, B. PARDINI, J. K. BURKS, H.. KATAYAMA, L. C. REINEKE, L. F. HUO, M. SYED, S. M. SONG, M. FERRACIN, E. OKI, B. FROMM, C. IVAN, K. BHUVANESHWAR, Y. GUSEV, K. MIMORI, D. MENTER, S. SEN, T. MATSUYAMA, H. UETAKE, C. VASILESCU, S. KOPETZ, J. PARKER-THORNBURG, A. TAGUCHI, S. M. HANASH, L. GIRNITA, Ondřej SLABÝ, A. GOEL, G. VARANI, M. GAGEA, C. L. LI, J. A. AJANI and G. A. CALIN. The Long Noncoding RNA CCAT2 Induces Chromosomal Instability Through BOP1-AURKB Signaling. \textit{Gastroenterology}. Philadelphia: W B Saunders co-Elsevier Inc, 2020, vol.~159, No~6, p.~2146-2195. ISSN~0016-5085. Available from: https://dx.doi.org/10.1053/j.gastro.2020.08.018.

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