Nuclear export of BATF2 enhances colorectal cancer proliferation through binding to CRM1
Abstract Background During the tumourigenesis and development of colorectal cancer (CRC), the inactivation of tumour suppressor genes is closely involved, although detailed molecular mechanisms remain elusive. Accumulating studies, including ours, have demonstrated that basic leucine zipper transcri...
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| Format: | Article |
| Language: | English |
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Wiley
2023-05-01
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| Series: | Clinical and Translational Medicine |
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| Online Access: | https://doi.org/10.1002/ctm2.1260 |
| _version_ | 1797817260451037184 |
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| author | Jie Zhou Zengjie Lei Jianfang Chen Shengbo Liao Yanrong Chen Chengxiang Liu Shuo Huang Liuli Li Yan Zhang Pei Wang Yinghui Huang Jianjun Li Houjie Liang |
| author_facet | Jie Zhou Zengjie Lei Jianfang Chen Shengbo Liao Yanrong Chen Chengxiang Liu Shuo Huang Liuli Li Yan Zhang Pei Wang Yinghui Huang Jianjun Li Houjie Liang |
| author_sort | Jie Zhou |
| collection | DOAJ |
| description | Abstract Background During the tumourigenesis and development of colorectal cancer (CRC), the inactivation of tumour suppressor genes is closely involved, although detailed molecular mechanisms remain elusive. Accumulating studies, including ours, have demonstrated that basic leucine zipper transcription factor ATF (activating transcription factor)‐like 2 (BATF2) is a capable tumour suppressor that localises in the nucleus. However, its different subcellular localisation, potential functions and underlying mechanisms are unclear. Methods The translocation of BATF2 and its clinical relevance were detected using CRC samples, cell lines and xenograft nude mice. Candidate BATF2‐binding proteins were screened using co‐immunoprecipitation, quantitative label‐free liquid chromatography–tandem mass spectrometry proteomic analysis, Western blotting and immunofluorescence. Recombinant plasmids, point mutations and siRNAs were applied to clarify the binding sites between BATF2 and chromosome region maintenance 1 (CRM1). Results The present study found that BATF2 was mainly localised in the cytoplasm, rather than nucleus, of CRC cells in vitro and in vivo, while cytoplasmic BATF2 expression was inversely correlated with the prognosis of CRC patients. Furthermore, we identified the nuclear export and subsequent ubiquitin‐mediated degradation of BATF2 in CRC cells. Mechanistically, a functional nuclear export sequence (any amino acid) was characterised in BATF2 protein, through which BATF2 bound to CRM1 and translocated out of nucleus, ultimately enhancing CRC growth via inducing activator protein 1 (AP‐1)/cyclin D1/phosphorylated retinoblastoma protein (pRb) signalling pathway. Additionally, nuclear export of BATF2 can be retarded by the mutation of NES in BATF2 or the knockdown of CRM1, whereas CRM1 expression was negatively associated with nuclear BATF2 expression and the prognosis of CRC patients. Conclusion These findings revealed the biological effects and underlying mechanisms of cytoplasmic localisation of BATF2. Furthermore, suppressing nuclear export of BATF2 via mutating its NES region or inhibiting CRM1 expression may serve as a promising therapeutic strategy against CRC. |
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| institution | Directory Open Access Journal |
| issn | 2001-1326 |
| language | English |
| last_indexed | 2024-03-13T08:51:03Z |
| publishDate | 2023-05-01 |
| publisher | Wiley |
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| series | Clinical and Translational Medicine |
| spelling | doaj.art-00556e9142d04deaaed07c5d2962aaf92023-05-29T11:28:30ZengWileyClinical and Translational Medicine2001-13262023-05-01135n/an/a10.1002/ctm2.1260Nuclear export of BATF2 enhances colorectal cancer proliferation through binding to CRM1Jie Zhou0Zengjie Lei1Jianfang Chen2Shengbo Liao3Yanrong Chen4Chengxiang Liu5Shuo Huang6Liuli Li7Yan Zhang8Pei Wang9Yinghui Huang10Jianjun Li11Houjie Liang12Department of Oncology and Southwest Cancer Center Southwest Hospital Army Medical University (Third Military Medical University) Chongqing ChinaDepartment of Medical Oncology Affiliated Jinling Hospital Medical School of Nanjing University Nanjing ChinaDepartment of Oncology and Southwest Cancer Center Southwest Hospital Army Medical University (Third Military Medical University) Chongqing ChinaDepartment of Otolaryngology People's Hospital of Xishui County Guizhou ChinaDepartment of Oncology and Southwest Cancer Center Southwest Hospital Army Medical University (Third Military Medical University) Chongqing ChinaDepartment of Oncology and Southwest Cancer Center Southwest Hospital Army Medical University (Third Military Medical University) Chongqing ChinaDepartment of Oncology and Southwest Cancer Center Southwest Hospital Army Medical University (Third Military Medical University) Chongqing ChinaDepartment of Oncology and Southwest Cancer Center Southwest Hospital Army Medical University (Third Military Medical University) Chongqing ChinaDepartment of Oncology and Southwest Cancer Center Southwest Hospital Army Medical University (Third Military Medical University) Chongqing ChinaDepartment of Oncology and Southwest Cancer Center Southwest Hospital Army Medical University (Third Military Medical University) Chongqing ChinaDepartment of Nephrology Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing Chongqing Clinical Research Center of Kidney and Urology Diseases Xinqiao Hospital Army Medical University Chongqing ChinaDepartment of Oncology and Southwest Cancer Center Southwest Hospital Army Medical University (Third Military Medical University) Chongqing ChinaDepartment of Oncology and Southwest Cancer Center Southwest Hospital Army Medical University (Third Military Medical University) Chongqing ChinaAbstract Background During the tumourigenesis and development of colorectal cancer (CRC), the inactivation of tumour suppressor genes is closely involved, although detailed molecular mechanisms remain elusive. Accumulating studies, including ours, have demonstrated that basic leucine zipper transcription factor ATF (activating transcription factor)‐like 2 (BATF2) is a capable tumour suppressor that localises in the nucleus. However, its different subcellular localisation, potential functions and underlying mechanisms are unclear. Methods The translocation of BATF2 and its clinical relevance were detected using CRC samples, cell lines and xenograft nude mice. Candidate BATF2‐binding proteins were screened using co‐immunoprecipitation, quantitative label‐free liquid chromatography–tandem mass spectrometry proteomic analysis, Western blotting and immunofluorescence. Recombinant plasmids, point mutations and siRNAs were applied to clarify the binding sites between BATF2 and chromosome region maintenance 1 (CRM1). Results The present study found that BATF2 was mainly localised in the cytoplasm, rather than nucleus, of CRC cells in vitro and in vivo, while cytoplasmic BATF2 expression was inversely correlated with the prognosis of CRC patients. Furthermore, we identified the nuclear export and subsequent ubiquitin‐mediated degradation of BATF2 in CRC cells. Mechanistically, a functional nuclear export sequence (any amino acid) was characterised in BATF2 protein, through which BATF2 bound to CRM1 and translocated out of nucleus, ultimately enhancing CRC growth via inducing activator protein 1 (AP‐1)/cyclin D1/phosphorylated retinoblastoma protein (pRb) signalling pathway. Additionally, nuclear export of BATF2 can be retarded by the mutation of NES in BATF2 or the knockdown of CRM1, whereas CRM1 expression was negatively associated with nuclear BATF2 expression and the prognosis of CRC patients. Conclusion These findings revealed the biological effects and underlying mechanisms of cytoplasmic localisation of BATF2. Furthermore, suppressing nuclear export of BATF2 via mutating its NES region or inhibiting CRM1 expression may serve as a promising therapeutic strategy against CRC.https://doi.org/10.1002/ctm2.1260BATF2colorectal cancerCRM1nuclear export |
| spellingShingle | Jie Zhou Zengjie Lei Jianfang Chen Shengbo Liao Yanrong Chen Chengxiang Liu Shuo Huang Liuli Li Yan Zhang Pei Wang Yinghui Huang Jianjun Li Houjie Liang Nuclear export of BATF2 enhances colorectal cancer proliferation through binding to CRM1 Clinical and Translational Medicine BATF2 colorectal cancer CRM1 nuclear export |
| title | Nuclear export of BATF2 enhances colorectal cancer proliferation through binding to CRM1 |
| title_full | Nuclear export of BATF2 enhances colorectal cancer proliferation through binding to CRM1 |
| title_fullStr | Nuclear export of BATF2 enhances colorectal cancer proliferation through binding to CRM1 |
| title_full_unstemmed | Nuclear export of BATF2 enhances colorectal cancer proliferation through binding to CRM1 |
| title_short | Nuclear export of BATF2 enhances colorectal cancer proliferation through binding to CRM1 |
| title_sort | nuclear export of batf2 enhances colorectal cancer proliferation through binding to crm1 |
| topic | BATF2 colorectal cancer CRM1 nuclear export |
| url | https://doi.org/10.1002/ctm2.1260 |
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