Super Enhancer-Mediated Upregulation of<i>HJURP</i>Promotes Growth and Survival of t(4;14)-Positive Multiple Myeloma

Jia, Yunlu; Zhou, Jianbiao; Tan, Tze King; Chung, Tae-Hoon; chen, yong xia; Chooi, Jing-Yuan; Sanda, Takaomi; Fullwood, Melissa J.; Xiong, Sinan; Toh, Sabrina Hui Min; Balan, Kalpnaa; Wong, Regina Wanju; Lim, Julia S.L.; Zhang, Enfan; Cai, Zhen; Shen, Peng; Chng, Wee Joo

doi:10.1158/0008-5472.can-21-0921

Cited by 25 publications

(20 citation statements)

References 50 publications

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“…HJURP overexpression effectively reversed the proapoptotic effect of SP600125 on BLUC cells, which was demonstrated by the dramatic decrease in the number of apoptotic cells in the HJURP activation + SP600125 group HJURP, a centromeric histone chaperone involved in de novo histone H3 variant CenH3 (CENP-A) recruitment (Niikura et al 2015), was one of the 25 overexpressed genes in BLUC based on biological information analyses, and HJURP expression was significantly higher in BLUC cell lines (SW780, 5637, T24 and TCCSUP) than BdECs. Similar expression of HJURP was also observed in many other cancers (Dou et al 2022, Jia et al 2022, Tsevegjav et al 2022. Notably, the mRNA and protein levels of HJURP were significantly upregulated in BCa tissues in a transcriptome and in vivo study (Cao et al 2017), which is consistent with the findings in the current study.…”

Section: Hjurp Mediates the Jnk/stat3 Signaling Pathway To Inhibit Bl...supporting

confidence: 91%

Effects of Holliday Junction-Recognition Protein-Mediated C-Jun N-Terminal Kinase/ Signal Transducer and Activator of Transcription 3 Signaling Pathway on Cell Proliferation, Cell Cycle and Cell Apoptosis in Bladder Urothelial Carcinoma

Gao

Zhou

et al. 2023

Tohoku J. Exp. Med.

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The Holliday Junction-Recognition Protein (HJURP) was upregulated in several tumors, which was associated with poor outcome. This study investigated the effects of the HJURP-mediated c-Jun Nterminal kinase (JNK)/ signal transducer and activator of transcription 3 (STAT3) pathway on bladder urothelial carcinoma (BLUC). Online databases were used to analyze HJURP expression in BLUC and the correlation of HJURP to JNK1 [mitogen-activated protein kinase 8 (MAPK8)], JNK2 (MAPK9), STAT3, marker of proliferation Ki-67 (MKI67), proliferating cell nuclear antigen (PCNA), cyclin dependent kinase 2 (CDK2), CDK4 and CDK6. HJURP expression was detected in BLUC cells and human normal primary bladder epithelial cells (BdECs). BLUC cells were treated with HJURP lentivirus activation /shRNA lentivirus particles or JNK inhibitor SP600125. HJURP was upregulated in BLUC tissues and correlated with poor prognosis of patients (all P < 0.05). HJURP in tumor positively correlated with MAPK8 (R = 0.30), MAPK9 (R = 0.30), STAT3 (R= 0.15), MKI67 (R= 0.60), PCNA (R= 0.46), CDK2 (R= 0.39), CDK4 (R= 0.24) and CDK6 (R= 0.21). SP600125 decreased p-JNK/JNK and p-STAT3/STAT3 in BLUC cells, which was reversed by HJURP overexpression (P < 0.05). The HJURP-mediated JNK/STAT3 pathway promoted BLUC cell proliferation and inhibited cell apoptosis (P < 0.05). HJURP reversed the arrested G0/G1 phase of BLUC cells by SP600125. HJURP acted as an oncogene to regulate BLUC cell proliferation, apoptosis and the cell cycle by mediating the JNK/STAT3 pathway. Therefore, HJURP targeting might be an attractive novel therapeutic target for early diagnosis and treatment in BLUC.

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Section: Hjurp Mediates the Jnk/stat3 Signaling Pathway To Inhibit Bl...supporting

confidence: 91%

Effects of Holliday Junction-Recognition Protein-Mediated C-Jun N-Terminal Kinase/ Signal Transducer and Activator of Transcription 3 Signaling Pathway on Cell Proliferation, Cell Cycle and Cell Apoptosis in Bladder Urothelial Carcinoma

Gao

Zhou

et al. 2023

Tohoku J. Exp. Med.

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“…Super-enhancers have been reported to be frequently associated with cancer genes [ 28 , 34 – 36 ]. Super-enhancer promotes the growth and survival of t(4;14)-positive multiple myeloma [ 16 ]. Super-enhancer was found to activate the Wnt/beta-catenin pathway and promotes the proliferation of liver cancer cells [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

“…Super-enhancers have been reported to be implicated in multiple types of cancers. Super-enhancer promotes the growth and survival of t(4;14)-positive multiple myeloma [ 16 ]. HJURP was reported to be an SE-associated gene in t(4;14)-positive multiple myeloma.…”

Section: Introductionmentioning

confidence: 99%

Super-enhancer profiling identifies novel critical and targetable cancer survival gene LYL1 in pediatric acute myeloid leukemia

Fang

Lü

Sang

et al. 2022

J Exp Clin Cancer Res

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Background Acute myeloid leukemia (AML) is a myeloid neoplasm makes up 7.6% of hematopoietic malignancies. Super-enhancers (SEs) represent a special group of enhancers, which have been reported in multiple cell types. In this study, we explored super-enhancer profiling through ChIP-Seq analysis of AML samples and AML cell lines, followed by functional analysis. Methods ChIP-seq analysis for H3K27ac was performed in 11 AML samples, 7 T-ALL samples, 8 B-ALL samples, and in NB4 cell line. Genes and pathways affected by GNE-987 treatment were identified by gene expression analysis using RNA-seq. One of the genes associated with super-enhancer and affected by GNE-987 treatment was LYL1 basic helix-loop-helix family member (LYL1). shRNA mediated gene interference was used to down-regulate the expression of LYL1 in AML cell lines, and knockdown efficiency was detected by RT-qPCR and western blotting. The effect of knockdown on the growth of AML cell lines was evaluated by CCK-8. Western blotting was used to detect PARP cleavage, and flow cytometry were used to determine the effect of knockdown on apoptosis of AML cells. Results We identified a total of 200 genes which were commonly associated with super-enhancers in ≧10 AML samples, and were found enriched in regulation of transcription. Using the BRD4 inhibitor GNE-987, we assessed the dependence of AML cells on transcriptional activation for growth and found GNE-987 treatment predominantly inhibits cell growth in AML cells. Moreover, 20 candidate genes were selected by super-enhancer profile and gene expression profile and among which LYL1 was observed to promote cell growth and survival in human AML cells. Conclusions In summary, we identified 200 common super-enhancer-associated genes in AML samples, and a series of those genes are cancer genes. We also found GNE-987 treatment downregulates the expression of super-enhancer-associated genes in AML cells, including the expression of LYL1. Further functional analysis indicated that LYL1 is required for AML cell growth and survival. These findings promote understanding of AML pathophysiology and elucidated an important role of LYL1 in AML progression.

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“…Additionally, SE profiling helps us to identify potential drug targets in various cancer types. For example, by profiling SEs in t(4;14)-translocated multiple myeloma, SE-associated gene HJURP was identified as a potential target as its silencing impaired cell growth and induced apoptosis [ 9 ]. Additionally, through mapping SEs in Acute Myeloid Leukemia (AML), a subtype of AML cells with SE-driven RARα was identified to be sensitive to RARα agonist SY-1425 [ 10 ].…”

Section: Constituents and Identification Of Super-enhancersmentioning

confidence: 99%

Super-Enhancers, Phase-Separated Condensates, and 3D Genome Organization in Cancer

Tang

Vijayakumar

Zhang

et al. 2022

Cancers

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3D chromatin organization plays an important role in transcription regulation and gene expression. The 3D genome is highly maintained by several architectural proteins, such as CTCF, Yin Yang 1, and cohesin complex. This structural organization brings regulatory DNA elements in close proximity to their target promoters. In this review, we discuss the 3D chromatin organization of super-enhancers and their relationship to phase-separated condensates. Super-enhancers are large clusters of DNA elements. They can physically contact with their target promoters by chromatin looping during transcription. Multiple transcription factors can bind to enhancer and promoter sequences and recruit a complex array of transcriptional co-activators and RNA polymerase II to effect transcriptional activation. Phase-separated condensates of transcription factors and transcriptional co-activators have been implicated in assembling the transcription machinery at particular enhancers. Cancer cells can hijack super-enhancers to drive oncogenic transcription to promote cell survival and proliferation. These dysregulated transcriptional programs can cause cancer cells to become highly dependent on transcriptional regulators, such as Mediator and BRD4. Moreover, the expression of oncogenes that are driven by super-enhancers is sensitive to transcriptional perturbation and often occurs in phase-separated condensates, supporting therapeutic rationales of targeting SE components, 3D genome organization, or dysregulated condensates in cancer.

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Super Enhancer-Mediated Upregulation ofHJURPPromotes Growth and Survival of t(4;14)-Positive Multiple Myeloma

Cited by 25 publications

References 50 publications

Effects of Holliday Junction-Recognition Protein-Mediated C-Jun N-Terminal Kinase/ Signal Transducer and Activator of Transcription 3 Signaling Pathway on Cell Proliferation, Cell Cycle and Cell Apoptosis in Bladder Urothelial Carcinoma

Effects of Holliday Junction-Recognition Protein-Mediated C-Jun N-Terminal Kinase/ Signal Transducer and Activator of Transcription 3 Signaling Pathway on Cell Proliferation, Cell Cycle and Cell Apoptosis in Bladder Urothelial Carcinoma

Super-enhancer profiling identifies novel critical and targetable cancer survival gene LYL1 in pediatric acute myeloid leukemia

Super-Enhancers, Phase-Separated Condensates, and 3D Genome Organization in Cancer

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