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SPT6 recruits SND1 to co‐activate human telomerase reverse transcriptase to promote colon cancer progression
Human telomerase reverse transcriptase (hTERT) plays an extremely important role in cancer initiation and development, including colorectal cancer (CRC). However, the precise upstream regulatory mechanisms of hTERT in different cancer types remain poorly understood. Here, we uncovered the candidate...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024721/ https://www.ncbi.nlm.nih.gov/pubmed/33305480 http://dx.doi.org/10.1002/1878-0261.12878 |
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author | Diao, Chaoliang Guo, Ping Yang, Wenjing Sun, Yao Liao, Yina Yan, Yue Zhao, Anshi Cai, Xin Hao, Jiaojiao Hu, Sheng Yu, Wendan Chen, Manyu Wang, Ruozhu Li, Wenyang Zuo, Yan Pan, Jinjin Hua, Chunyu Lu, Xiaona Fan, Wenhua Zheng, Zongheng Deng, Wuguo Luo, Guangyu Guo, Wei |
author_facet | Diao, Chaoliang Guo, Ping Yang, Wenjing Sun, Yao Liao, Yina Yan, Yue Zhao, Anshi Cai, Xin Hao, Jiaojiao Hu, Sheng Yu, Wendan Chen, Manyu Wang, Ruozhu Li, Wenyang Zuo, Yan Pan, Jinjin Hua, Chunyu Lu, Xiaona Fan, Wenhua Zheng, Zongheng Deng, Wuguo Luo, Guangyu Guo, Wei |
author_sort | Diao, Chaoliang |
collection | PubMed |
description | Human telomerase reverse transcriptase (hTERT) plays an extremely important role in cancer initiation and development, including colorectal cancer (CRC). However, the precise upstream regulatory mechanisms of hTERT in different cancer types remain poorly understood. Here, we uncovered the candidate transcriptional factor of hTERT in CRC and explored its role and the corresponding molecular mechanisms in regulating hTERT expression and CRC survival with an aim of developing mechanism‐based combinational targeting therapy. The possible binding proteins at the hTERT promoter were uncovered using pull‐down/mass spectrometry analysis. The regulation of SPT6 on hTERT expression and CRC survival was evaluated in human CRC cell lines and mouse models. Mechanistic studies focusing on the synergy between SPT6 and staphylococcal nuclease and Tudor domain containing 1 (SND1) in controlling hTERT expression and CRC progression were conducted also in the above two levels. The expression correlation and clinical significance of SPT6, SND1, and hTERT were investigated in tumor tissues from murine models and patients with CRC in situ. SPT6 was identified as a possible transcriptional factor to bind to the hTERT promoter. SPT6 knockdown decreased the activity of hTERT promoter, downregulated the protein expression level of hTERT, suppressed proliferation, invasion, and stem‐like properties, promoted apoptosis induction, and enhanced chemotherapeutic drug sensitivity in vitro. SPT6 silencing also led to the delay of tumor growth and metastasis in mice carrying xenografts of human‐derived colon cancer cells. Mechanistically, SND1 interacted with SPT6 to co‐control hTERT expression and CRC cell proliferation, stemness, and growth in vitro and in vivo. SPT6, SND1, and hTERT were highly expressed simultaneously in CRC tissues, both from the murine model and patients with CRC in situ, and pairwise expression among these three factors showed a significant positive correlation. In brief, our research demonstrated that SPT6 synergized with SND1 to promote CRC development by targeting hTERT and put forward that inhibiting the SPT6‐SND1‐hTERT axis may create a therapeutic vulnerability in CRC. |
format | Online Article Text |
id | pubmed-8024721 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-80247212021-04-12 SPT6 recruits SND1 to co‐activate human telomerase reverse transcriptase to promote colon cancer progression Diao, Chaoliang Guo, Ping Yang, Wenjing Sun, Yao Liao, Yina Yan, Yue Zhao, Anshi Cai, Xin Hao, Jiaojiao Hu, Sheng Yu, Wendan Chen, Manyu Wang, Ruozhu Li, Wenyang Zuo, Yan Pan, Jinjin Hua, Chunyu Lu, Xiaona Fan, Wenhua Zheng, Zongheng Deng, Wuguo Luo, Guangyu Guo, Wei Mol Oncol Research Articles Human telomerase reverse transcriptase (hTERT) plays an extremely important role in cancer initiation and development, including colorectal cancer (CRC). However, the precise upstream regulatory mechanisms of hTERT in different cancer types remain poorly understood. Here, we uncovered the candidate transcriptional factor of hTERT in CRC and explored its role and the corresponding molecular mechanisms in regulating hTERT expression and CRC survival with an aim of developing mechanism‐based combinational targeting therapy. The possible binding proteins at the hTERT promoter were uncovered using pull‐down/mass spectrometry analysis. The regulation of SPT6 on hTERT expression and CRC survival was evaluated in human CRC cell lines and mouse models. Mechanistic studies focusing on the synergy between SPT6 and staphylococcal nuclease and Tudor domain containing 1 (SND1) in controlling hTERT expression and CRC progression were conducted also in the above two levels. The expression correlation and clinical significance of SPT6, SND1, and hTERT were investigated in tumor tissues from murine models and patients with CRC in situ. SPT6 was identified as a possible transcriptional factor to bind to the hTERT promoter. SPT6 knockdown decreased the activity of hTERT promoter, downregulated the protein expression level of hTERT, suppressed proliferation, invasion, and stem‐like properties, promoted apoptosis induction, and enhanced chemotherapeutic drug sensitivity in vitro. SPT6 silencing also led to the delay of tumor growth and metastasis in mice carrying xenografts of human‐derived colon cancer cells. Mechanistically, SND1 interacted with SPT6 to co‐control hTERT expression and CRC cell proliferation, stemness, and growth in vitro and in vivo. SPT6, SND1, and hTERT were highly expressed simultaneously in CRC tissues, both from the murine model and patients with CRC in situ, and pairwise expression among these three factors showed a significant positive correlation. In brief, our research demonstrated that SPT6 synergized with SND1 to promote CRC development by targeting hTERT and put forward that inhibiting the SPT6‐SND1‐hTERT axis may create a therapeutic vulnerability in CRC. John Wiley and Sons Inc. 2021-01-12 2021-04 /pmc/articles/PMC8024721/ /pubmed/33305480 http://dx.doi.org/10.1002/1878-0261.12878 Text en © 2020 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Articles Diao, Chaoliang Guo, Ping Yang, Wenjing Sun, Yao Liao, Yina Yan, Yue Zhao, Anshi Cai, Xin Hao, Jiaojiao Hu, Sheng Yu, Wendan Chen, Manyu Wang, Ruozhu Li, Wenyang Zuo, Yan Pan, Jinjin Hua, Chunyu Lu, Xiaona Fan, Wenhua Zheng, Zongheng Deng, Wuguo Luo, Guangyu Guo, Wei SPT6 recruits SND1 to co‐activate human telomerase reverse transcriptase to promote colon cancer progression |
title | SPT6 recruits SND1 to co‐activate human telomerase reverse transcriptase to promote colon cancer progression |
title_full | SPT6 recruits SND1 to co‐activate human telomerase reverse transcriptase to promote colon cancer progression |
title_fullStr | SPT6 recruits SND1 to co‐activate human telomerase reverse transcriptase to promote colon cancer progression |
title_full_unstemmed | SPT6 recruits SND1 to co‐activate human telomerase reverse transcriptase to promote colon cancer progression |
title_short | SPT6 recruits SND1 to co‐activate human telomerase reverse transcriptase to promote colon cancer progression |
title_sort | spt6 recruits snd1 to co‐activate human telomerase reverse transcriptase to promote colon cancer progression |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024721/ https://www.ncbi.nlm.nih.gov/pubmed/33305480 http://dx.doi.org/10.1002/1878-0261.12878 |
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