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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for Cancer Research 2022
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.
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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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