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Super Enhancer-Mediated Upregulation of HJURP Promotes Growth and Survival of t(4;14)-Positive Multiple Myeloma
Multiple myeloma is an incurable malignancy with marked clinical and genetic heterogeneity. The cytogenetic abnormality t(4;14) (p16.3;q32.3) confers aggressive behavior in multiple myeloma. Recently, essential oncogenic drivers in a wide range of cancers have been shown to be controlled by super-en...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for Cancer Research
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9397631/ https://www.ncbi.nlm.nih.gov/pubmed/34893510 http://dx.doi.org/10.1158/0008-5472.CAN-21-0921 |
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author | Jia, Yunlu Zhou, Jianbiao Tan, Tze King Chung, Tae-Hoon Chen, Yongxia Chooi, Jing-Yuan Sanda, Takaomi Fullwood, Melissa J. Xiong, Sinan Toh, Sabrina H.M. Balan, Kalpnaa Wong, Regina W.J. Lim, Julia S.L. Zhang, Enfan Cai, Zhen Shen, Peng Chng, Wee Joo |
author_facet | Jia, Yunlu Zhou, Jianbiao Tan, Tze King Chung, Tae-Hoon Chen, Yongxia Chooi, Jing-Yuan Sanda, Takaomi Fullwood, Melissa J. Xiong, Sinan Toh, Sabrina H.M. Balan, Kalpnaa Wong, Regina W.J. Lim, Julia S.L. Zhang, Enfan Cai, Zhen Shen, Peng Chng, Wee Joo |
author_sort | Jia, Yunlu |
collection | PubMed |
description | Multiple myeloma is an incurable malignancy with marked clinical and genetic heterogeneity. The cytogenetic abnormality t(4;14) (p16.3;q32.3) confers aggressive behavior in multiple myeloma. Recently, essential oncogenic drivers in a wide range of cancers have been shown to be controlled by super-enhancers (SE). We used chromatin immunoprecipitation sequencing of the active enhancer marker histone H3 lysine 27 acetylation (H3K27ac) to profile unique SEs in t(4;14)-translocated multiple myeloma. The histone chaperone HJURP was aberrantly overexpressed in t(4;14)-positive multiple myeloma due to transcriptional activation by a distal SE induced by the histone lysine methyltransferase NSD2. Silencing of HJURP with short hairpin RNA or CRISPR interference of SE function impaired cell viability and led to apoptosis. Conversely, HJURP overexpression promoted cell proliferation and abrogated apoptosis. Mechanistically, the NSD2/BRD4 complex positively coregulated HJURP transcription by binding the promoter and active elements of its SE. In summary, this study introduces SE profiling as an efficient approach to identify new targets and understand molecular pathogenesis in specific subtypes of cancer. Moreover, HJURP could be a valuable therapeutic target in patients with t(4;14)-positive myeloma. SIGNIFICANCE: A super-enhancer screen in t(4;14) multiple myeloma serves to identify genes that promote growth and survival of myeloma cells, which may be evaluated in future studies as therapeutic targets. |
format | Online Article Text |
id | pubmed-9397631 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Association for Cancer Research |
record_format | MEDLINE/PubMed |
spelling | pubmed-93976312023-01-05 Super Enhancer-Mediated Upregulation of HJURP Promotes Growth and Survival of t(4;14)-Positive Multiple Myeloma Jia, Yunlu Zhou, Jianbiao Tan, Tze King Chung, Tae-Hoon Chen, Yongxia Chooi, Jing-Yuan Sanda, Takaomi Fullwood, Melissa J. Xiong, Sinan Toh, Sabrina H.M. Balan, Kalpnaa Wong, Regina W.J. Lim, Julia S.L. Zhang, Enfan Cai, Zhen Shen, Peng Chng, Wee Joo Cancer Res Molecular Cell Biology Multiple myeloma is an incurable malignancy with marked clinical and genetic heterogeneity. The cytogenetic abnormality t(4;14) (p16.3;q32.3) confers aggressive behavior in multiple myeloma. Recently, essential oncogenic drivers in a wide range of cancers have been shown to be controlled by super-enhancers (SE). We used chromatin immunoprecipitation sequencing of the active enhancer marker histone H3 lysine 27 acetylation (H3K27ac) to profile unique SEs in t(4;14)-translocated multiple myeloma. The histone chaperone HJURP was aberrantly overexpressed in t(4;14)-positive multiple myeloma due to transcriptional activation by a distal SE induced by the histone lysine methyltransferase NSD2. Silencing of HJURP with short hairpin RNA or CRISPR interference of SE function impaired cell viability and led to apoptosis. Conversely, HJURP overexpression promoted cell proliferation and abrogated apoptosis. Mechanistically, the NSD2/BRD4 complex positively coregulated HJURP transcription by binding the promoter and active elements of its SE. In summary, this study introduces SE profiling as an efficient approach to identify new targets and understand molecular pathogenesis in specific subtypes of cancer. Moreover, HJURP could be a valuable therapeutic target in patients with t(4;14)-positive myeloma. SIGNIFICANCE: A super-enhancer screen in t(4;14) multiple myeloma serves to identify genes that promote growth and survival of myeloma cells, which may be evaluated in future studies as therapeutic targets. American Association for Cancer Research 2022-02-01 2021-12-10 /pmc/articles/PMC9397631/ /pubmed/34893510 http://dx.doi.org/10.1158/0008-5472.CAN-21-0921 Text en ©2021 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license. |
spellingShingle | Molecular Cell Biology Jia, Yunlu Zhou, Jianbiao Tan, Tze King Chung, Tae-Hoon Chen, Yongxia Chooi, Jing-Yuan Sanda, Takaomi Fullwood, Melissa J. Xiong, Sinan Toh, Sabrina H.M. Balan, Kalpnaa Wong, Regina W.J. Lim, Julia S.L. Zhang, Enfan Cai, Zhen Shen, Peng Chng, Wee Joo Super Enhancer-Mediated Upregulation of HJURP Promotes Growth and Survival of t(4;14)-Positive Multiple Myeloma |
title | Super Enhancer-Mediated Upregulation of HJURP Promotes Growth and Survival of t(4;14)-Positive Multiple Myeloma |
title_full | Super Enhancer-Mediated Upregulation of HJURP Promotes Growth and Survival of t(4;14)-Positive Multiple Myeloma |
title_fullStr | Super Enhancer-Mediated Upregulation of HJURP Promotes Growth and Survival of t(4;14)-Positive Multiple Myeloma |
title_full_unstemmed | Super Enhancer-Mediated Upregulation of HJURP Promotes Growth and Survival of t(4;14)-Positive Multiple Myeloma |
title_short | Super Enhancer-Mediated Upregulation of HJURP Promotes Growth and Survival of t(4;14)-Positive Multiple Myeloma |
title_sort | super enhancer-mediated upregulation of hjurp promotes growth and survival of t(4;14)-positive multiple myeloma |
topic | Molecular Cell Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9397631/ https://www.ncbi.nlm.nih.gov/pubmed/34893510 http://dx.doi.org/10.1158/0008-5472.CAN-21-0921 |
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