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SOX9 is a key component of RUNX2-regulated transcriptional circuitry in osteosarcoma

BACKGROUND: The absence of prominent, actionable genetic alternations in osteosarcomas (OS) implies that transcriptional and epigenetic mechanisms significantly contribute to the progression of this life-threatening form of cancer. Therefore, the identification of potential transcriptional events th...

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Autores principales: Kim, Young-Im, Tseng, Yu-Chou, Ayaz, Gamze, Wang, Shasha, Yan, Hualong, du Bois, Wendy, Yang, Howard, Zhen, Tao, Lee, Maxwell P., Liu, Paul, Kaplan, Rosandra N., Huang, Jing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10367263/
https://www.ncbi.nlm.nih.gov/pubmed/37491298
http://dx.doi.org/10.1186/s13578-023-01088-2
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author Kim, Young-Im
Tseng, Yu-Chou
Ayaz, Gamze
Wang, Shasha
Yan, Hualong
du Bois, Wendy
Yang, Howard
Zhen, Tao
Lee, Maxwell P.
Liu, Paul
Kaplan, Rosandra N.
Huang, Jing
author_facet Kim, Young-Im
Tseng, Yu-Chou
Ayaz, Gamze
Wang, Shasha
Yan, Hualong
du Bois, Wendy
Yang, Howard
Zhen, Tao
Lee, Maxwell P.
Liu, Paul
Kaplan, Rosandra N.
Huang, Jing
author_sort Kim, Young-Im
collection PubMed
description BACKGROUND: The absence of prominent, actionable genetic alternations in osteosarcomas (OS) implies that transcriptional and epigenetic mechanisms significantly contribute to the progression of this life-threatening form of cancer. Therefore, the identification of potential transcriptional events that promote the survival of OS cells could be key in devising targeted therapeutic approaches for OS. We have previously shown that RUNX2 is a transcription factor (TF) essential for OS cell survival. Unfortunately, the transcriptional network or circuitry regulated by RUNX2 in OS cells is still largely unknown. METHODS: The TFs that are in the RUNX2 transcriptional circuitry were identified by analyzing RNAseq and ChIPseq datasets of RUNX2. To evaluate the effect of SOX9 knockdown on the survival of osteosarcoma cells in vitro, we employed cleaved caspase-3 immunoblotting and propidium iodide staining techniques. The impact of SOX9 and JMJD1C depletion on OS tumor growth was examined in vivo using xenografts and immunohistochemistry. Downstream targets of SOX9 were identified and dissected using RNAseq, pathway analysis, and gene set enrichment analysis. Furthermore, the interactome of SOX9 was identified using BioID and validated by PLA. RESULT: Our findings demonstrate that SOX9 is a critical TF that is induced by RUNX2. Both in vitro and in vivo experiments revealed that SOX9 plays a pivotal role in the survival of OS. RNAseq analysis revealed that SOX9 activates the transcription of MYC, a downstream target of RUNX2. Mechanistically, our results suggest a transcriptional network involving SOX9, RUNX2, and MYC, with SOX9 binding to RUNX2. Moreover, we discovered that JMJD1C, a chromatin factor, is a novel binding partner of SOX9, and depletion of JMJD1C impairs OS tumor growth. CONCLUSION: The findings of this study represent a significant advancement in our understanding of the transcriptional network present in OS cells, providing valuable insights that may contribute to the development of targeted therapies for OS. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13578-023-01088-2.
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spelling pubmed-103672632023-07-26 SOX9 is a key component of RUNX2-regulated transcriptional circuitry in osteosarcoma Kim, Young-Im Tseng, Yu-Chou Ayaz, Gamze Wang, Shasha Yan, Hualong du Bois, Wendy Yang, Howard Zhen, Tao Lee, Maxwell P. Liu, Paul Kaplan, Rosandra N. Huang, Jing Cell Biosci Research BACKGROUND: The absence of prominent, actionable genetic alternations in osteosarcomas (OS) implies that transcriptional and epigenetic mechanisms significantly contribute to the progression of this life-threatening form of cancer. Therefore, the identification of potential transcriptional events that promote the survival of OS cells could be key in devising targeted therapeutic approaches for OS. We have previously shown that RUNX2 is a transcription factor (TF) essential for OS cell survival. Unfortunately, the transcriptional network or circuitry regulated by RUNX2 in OS cells is still largely unknown. METHODS: The TFs that are in the RUNX2 transcriptional circuitry were identified by analyzing RNAseq and ChIPseq datasets of RUNX2. To evaluate the effect of SOX9 knockdown on the survival of osteosarcoma cells in vitro, we employed cleaved caspase-3 immunoblotting and propidium iodide staining techniques. The impact of SOX9 and JMJD1C depletion on OS tumor growth was examined in vivo using xenografts and immunohistochemistry. Downstream targets of SOX9 were identified and dissected using RNAseq, pathway analysis, and gene set enrichment analysis. Furthermore, the interactome of SOX9 was identified using BioID and validated by PLA. RESULT: Our findings demonstrate that SOX9 is a critical TF that is induced by RUNX2. Both in vitro and in vivo experiments revealed that SOX9 plays a pivotal role in the survival of OS. RNAseq analysis revealed that SOX9 activates the transcription of MYC, a downstream target of RUNX2. Mechanistically, our results suggest a transcriptional network involving SOX9, RUNX2, and MYC, with SOX9 binding to RUNX2. Moreover, we discovered that JMJD1C, a chromatin factor, is a novel binding partner of SOX9, and depletion of JMJD1C impairs OS tumor growth. CONCLUSION: The findings of this study represent a significant advancement in our understanding of the transcriptional network present in OS cells, providing valuable insights that may contribute to the development of targeted therapies for OS. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13578-023-01088-2. BioMed Central 2023-07-25 /pmc/articles/PMC10367263/ /pubmed/37491298 http://dx.doi.org/10.1186/s13578-023-01088-2 Text en © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Kim, Young-Im
Tseng, Yu-Chou
Ayaz, Gamze
Wang, Shasha
Yan, Hualong
du Bois, Wendy
Yang, Howard
Zhen, Tao
Lee, Maxwell P.
Liu, Paul
Kaplan, Rosandra N.
Huang, Jing
SOX9 is a key component of RUNX2-regulated transcriptional circuitry in osteosarcoma
title SOX9 is a key component of RUNX2-regulated transcriptional circuitry in osteosarcoma
title_full SOX9 is a key component of RUNX2-regulated transcriptional circuitry in osteosarcoma
title_fullStr SOX9 is a key component of RUNX2-regulated transcriptional circuitry in osteosarcoma
title_full_unstemmed SOX9 is a key component of RUNX2-regulated transcriptional circuitry in osteosarcoma
title_short SOX9 is a key component of RUNX2-regulated transcriptional circuitry in osteosarcoma
title_sort sox9 is a key component of runx2-regulated transcriptional circuitry in osteosarcoma
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10367263/
https://www.ncbi.nlm.nih.gov/pubmed/37491298
http://dx.doi.org/10.1186/s13578-023-01088-2
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