DHX15 is up‐regulated in castration‐resistant prostate cancer and required for androgen receptor sensitivity to low DHT concentrations

Xu, Yadong; Song, Qiong; Pascal, Laura E.; Zhong, Mingming; Zhou, Yibin; Zhou, Jianhua; Deng, Fang−Ming; Huang, Jiaoti; Wang, Zhou

doi:10.1002/pros.23773

Cited by 11 publications

(12 citation statements)

References 45 publications

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“…Studies by Xu et al 17 and Jing et al 15 revealed the roles of DHX15 in prostate progression. DHX15 is upregulated in castration‐resistant prostate cancer by interacting with the androgen receptor 15,17 . DHX15 overexpression is also found in hepatocellular carcinoma and is associated with an aggressive phenotype of cancer 16 .…”

Section: Introductionmentioning

confidence: 99%

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Dhx15 regulates zebrafish definitive hematopoiesis through the unfolded protein response pathway

et al. 2021

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Gene alterations are recognized as important events in acute myeloid leukemia (AML) progression. Studies on hematopoiesis of altered genes contribute to a better understanding on their roles in AML progression. Our previous work reported a DEAH box helicase 15 (DHX15) R222G mutation in AML patients, and we showed DHX15 overexpression is associated with poor prognosis in AML patients. In this work, we further study the role of dhx15 in zebrafish developmental hematopoiesis by generating dhx15−/− zebrafish using transcription activator‐like effector nuclease technology. Whole‐mount in situ hybridization (WISH) analysis showed hematopoietic stem/progenitor cells were dramatically perturbed when dhx15 was deleted. Immunofluorescence staining indicated inhibited hematopoietic stem/progenitor cell (HSPC) proliferation instead of accelerated apoptosis were detected in dhx15−/− zebrafish. Furthermore, our data showed that HSPC defect is mediated through the unfolded protein response (UPR) pathway. DHX15 R222G mutation, a recurrent mutation identified in AML patients, displayed a compromised function in restoring HSPC failure in dhx15−/−; Tg (hsp: DHX15 R222G) zebrafish. Collectively, this work revealed a vital role of dhx15 in the maintenance of definitive hematopoiesis in zebrafish through the unfolded protein respone pathway. The study of DHX15 and DHX15 R222G mutation could hold clinical significance for evaluating prognosis of AML patients with aberrant DHX15 expression.

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Section: Introductionmentioning

confidence: 99%

“…12,13 Recent studies indicate DHX15 correlates with cancer development. [14][15][16] Studies by Xu et al 17 and Jing et al 15 revealed the roles of DHX15 in prostate progression. DHX15 is upregulated in castration-resistant prostate cancer by interacting with the androgen receptor.…”

Section: Introductionmentioning

confidence: 99%

Dhx15 regulates zebrafish definitive hematopoiesis through the unfolded protein response pathway

et al. 2021

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“…DHX15 knockdown in PC cells reduced the expression of AR target genes, including KLK3 (PSA), TMPRSS 2, NKX3.1 and SCL45A3 , indicating an important role for DHX15 in regulating the expression of a subset of AR downstream genes [ 49 ]. Notably, DHX15 was shown to be upregulated in PC and its expression was highly correlated with Gleason scores and PSA recurrence [ 49 , 51 ]. Furthermore, DHX15 knockdown reduced AR sensitivity to DHT and inhibited cell growth at low DHT levels, enhancing enzalutamide inhibition of growth in the androgen-resistant C4–2 cell line [ 51 ].…”

Section: Discussionmentioning

confidence: 99%

“…Notably, DHX15 was shown to be upregulated in PC and its expression was highly correlated with Gleason scores and PSA recurrence [ 49 , 51 ]. Furthermore, DHX15 knockdown reduced AR sensitivity to DHT and inhibited cell growth at low DHT levels, enhancing enzalutamide inhibition of growth in the androgen-resistant C4–2 cell line [ 51 ]. These observations suggest that DHX15 upregulation in PC could contribute to cancer progression and castration resistance.…”

Section: Discussionmentioning

confidence: 99%

The DNA/RNA helicase DHX9 contributes to the transcriptional program of the androgen receptor in prostate cancer

Chellini

Pieraccioli

Sette

et al. 2022

J Exp Clin Cancer Res

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Background Prostate cancer (PC) is the most commonly diagnosed male malignancy and an important cause of mortality. Androgen deprivation therapy is the first line treatment but, unfortunately, a large part of patients evolves to a castration-resistant stage, for which no effective cure is currently available. The DNA/RNA helicase DHX9 is emerging as an important regulator of cellular processes that are often deregulated in cancer. Methods To investigate whether DHX9 modulates PC cell transcriptome we performed RNA-sequencing analyses upon DHX9 silencing in the androgen-responsive cell line LNCaP. Bioinformatics and functional analyses were carried out to elucidate the mechanism of gene expression regulation by DHX9. Data from The Cancer Genome Atlas were mined to evaluate the potential role of DHX9 in PC. Results We found that up-regulation of DHX9 correlates with advanced stage and is associated with poor prognosis of PC patients. High-throughput RNA-sequencing analysis revealed that depletion of DHX9 in androgen-sensitive LNCaP cells affects expression of hundreds of genes, which significantly overlap with known targets of the Androgen Receptor (AR). Notably, AR binds to the DHX9 promoter and induces its expression, while Enzalutamide-mediated inhibition of AR activity represses DHX9 expression. Moreover, DHX9 interacts with AR in LNCaP cells and its depletion significantly reduced the recruitment of AR to the promoter region of target genes and the ability of AR to promote their expression in response to 5α-dihydrotestosterone. Consistently, silencing of DXH9 negatively affected androgen-induced PC cell proliferation and migration. Conclusions Collectively, our data uncover a new role of DHX9 in the control of the AR transcriptional program and establish the existence of an oncogenic DHX9/AR axis, which may represent a new druggable target to counteract PC progression.

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“…DHX15 is involved in the regulation of tumor cell growth and is thereby identified as a coactivator of prostate tumor progression [28]. In addition, DHX15 activation plays a positive role in bone defect regeneration [29].…”

Section: Discussionmentioning

confidence: 99%

Cellular Processes Involved in Jurkat Cells Exposed to Nanosecond Pulsed Electric Field

Liu

Yang

et al. 2019

IJMS

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Recently, nanosecond pulsed electric field (nsPEF) has been considered as a new tool for tumor therapy, but its molecular mechanism of function remains to be fully elucidated. Here, we explored the cellular processes of Jurkat cells exposed to nanosecond pulsed electric field. Differentially expressed genes (DEGs) were acquired from the GEO2R, followed by analysis with a series of bioinformatics tools. Subsequently, 3D protein models of hub genes were modeled by Modeller 9.21 and Rosetta 3.9. Then, a 100 ns molecular dynamics simulation for each hub protein was performed with GROMACS 2018.2. Finally, three kinds of nsPEF voltages (0.01, 0.05, and 0.5 mV/mm) were used to simulate the molecular dynamics of hub proteins for 100 ns. A total of 1769 DEGs and eight hub genes were obtained. Molecular dynamic analysis, including root mean square deviation (RMSD), root mean square fluctuation (RMSF), and the Rg, demonstrated that the 3D structure of hub proteins was built, and the structural characteristics of hub proteins under different nsPEFs were acquired. In conclusion, we explored the effect of nsPEF on Jurkat cell signaling pathway from the perspective of molecular informatics, which will be helpful in understanding the complex effects of nsPEF on acute T-cell leukemia Jurkat cells.

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DHX15 is up‐regulated in castration‐resistant prostate cancer and required for androgen receptor sensitivity to low DHT concentrations

Cited by 11 publications

References 45 publications

Dhx15 regulates zebrafish definitive hematopoiesis through the unfolded protein response pathway

Dhx15 regulates zebrafish definitive hematopoiesis through the unfolded protein response pathway

The DNA/RNA helicase DHX9 contributes to the transcriptional program of the androgen receptor in prostate cancer

Cellular Processes Involved in Jurkat Cells Exposed to Nanosecond Pulsed Electric Field

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