KDM3A/Ets1 epigenetic axis contributes to PAX3/FOXO1‐driven and independent disease‐promoting gene expression in fusion‐positive Rhabdomyosarcoma

Sobral, Lays Martin; Hicks, Hannah M.; Parrish, Janet K.; McCann, Tyler; Hsieh, Joseph; Goodspeed, Andrew; Costello, James C.; Black, Joshua C.; Jedlicka, Paul

doi:10.1002/1878-0261.12769

Cited by 5 publications

(2 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The transcriptional activity of ets1 has been reported to be regulated by epigenetic modifications (Liu et al 2020;Sobral et al 2020). The present study represented an association between KMT5A and ets1 (Fig.…”

Section: Discussionsupporting

confidence: 71%

ets1 associates with KMT5A to participate in high glucose-mediated EndMT via upregulation of PFN2 expression in diabetic nephropathy

Zhong

et al. 2021

Mol Med

View full text Add to dashboard Cite

Background Diabetic nephropathy (DN) is currently the leading cause of end-stage renal disease globally. The endothelial-to-mesenchymal transition (EndMT) of glomerular endothelial cells has been reported to play a crucial role in DN. As a specific form of epithelial-to-mesenchymal transition, EndMT and epithelial-to-mesenchymal transition may exhibit mutual modulators. Profilin 2 (PFN2) has been reported to participate in epithelial-to-mesenchymal transition. Moreover, ETS proto-oncogene 1 (ets1) and lysine methyltransferase 5A (KMT5A) have been reported to contribute to high glucose-mediated endothelial injury and epithelial-to-mesenchymal transition. In this study, we hypothesize ets1 associates with KMT5A to modulate PFN2 transcription, thus participating in high glucose-mediated EndMT in glomerular endothelial cells. Methods Immunohistochemistry (IHC) was performed to detect protein levels in the kidney tissues and/or aorta tissues of human subjects and rats. Western blot, qPCR and immunofluorescence were performed using human umbilical vein endothelial cells (HUVECs). Chromatin immunoprecipitation (ChIP) assays and dual luciferase assays were performed to assess transcriptional activity. The difference between the groups was compared by two-tailed unpaired t-tests or one-way ANOVAs. Results Our data indicated that vimentin, αSMA, S100A4 and PFN2 levels were increased, and CD31 levels were reduced in glomerular endothelial cells of DN patients and rats. Our cell experiments showed that high glucose induced EndMT by augmenting PFN2 expression in HUVECs. Moreover, high glucose increased ets1 expression. si-ets1 suppressed high glucose-induced PFN2 levels and EndMT. ets1 overexpression-mediated EndMT was reversed by si-PFN2. Furthermore, ets1 was determined to associate with KMT5A. High glucose attenuated KMT5A levels and histone H4 lysine 20 methylation (H4K20me1), one of the downstream targets of KMT5A. KMT5A upregulation suppressed high glucose-induced PFN2 levels and EndMT. sh-KMT5A-mediated EndMT was counteracted by si-PFN2. Furthermore, H4K20me1 and ets1 occupied the PFN2 promoter region. sh-KMT5A cooperated with ets1 overexpression to activate PFN2 promoter activity. Our in vivo study demonstrated that KMT5A was reduced, while ets1 was augmented, in glomerular endothelial cells of DN patients and rats. Conclusions The present study indicated that ets1 cooperated with KMT5A to transcribe PFN2, thus contributing to hyperglycemia-induced EndMT in the glomerular endothelial cells of DN patients and rats. Trial registration ChiCTR, ChiCTR2000029425. 2020/1/31, http://www.chictr.org.cn/showproj.aspx?proj=48548

show abstract

Section: Discussionsupporting

confidence: 71%

ets1 associates with KMT5A to participate in high glucose-mediated EndMT via upregulation of PFN2 expression in diabetic nephropathy

Zhong

et al. 2021

Mol Med

View full text Add to dashboard Cite

show abstract

“…A significant positive correlation between KDM5A and ETS1 was confirmed in PRAD tissues. ETS1 has been found to be activated by KDM3A through epigenetic regulation (Sechler et al 2017; Sobral et al 2020). Importantly, we observed that KDM5A knockdown in cells led to an increase in H3K4me2 expression whereas a decline in ETS1 expression, indicating that KDM5A enhances ETS1 expression through the demethylation of H3K4me2.…”

Section: Discussionmentioning

confidence: 99%

Lysine demethylase 5A promotes prostate adenocarcinoma progression by suppressing microRNA-330-3p expression and activating the COPB2/PI3K/AKT axis in an ETS1-dependent manner

Zhang

Sun

et al. 2022

J. Cell Commun. Signal.

View full text Add to dashboard Cite

Lysine demethylase 5A (KDM5A) is a histone demethylase frequently involved in cancer progression. This research aimed to explore the function of KDM5A in prostate adenocarcinoma (PRAD) and the molecular mechanism. KDM5A was highly expressed in collected PRAD tissues and acquired PRAD cells. High KDM5A expression was correlated with reduced survival and poor prognosis of patients with PRAD. Knockdown of KDM5A suppressed the proliferation, colony formation, migration, and invasiveness of PRAD cells and reduced angiogenesis ability of endothelial cells. Downstream molecules implicated in KDM5A mediation were predicted using integrated bioinformatic analyses. KDM5A enhanced ETS protooncogene 1 (ETS1) expression through demethylation of H3K4me2 at its promoter. ETS1 suppressed the transcription activity of miR-330-3p, and either further ETS1 overexpression or miR-330-3p inhibition blocked the functions of KDM5A knockdown in PRAD. miR-330-3p targeted coatomer protein complex subunit β2 (COPB2) mRNA. Downregulation of miR-330-3p restored the expression of COPB2 and activated the PI3K/AKT pathway in PRAD. The results in vitro were reproduced in vivo where KDM5A downregulation suppressed the growth and metastasis of xenograft tumors in nude mice.In conclusion, this study demonstrated that KDM5A promoted PRAD by suppressing miR-330-3p and activating the COPB2/ PI3K/AKT axis in an ETS1-dependent manner.

show abstract

RGL2 as an age-dependent factor regulates colon cancer progression

Cheng

Xia

et al. 2021

Computational and Structural Biotechnology Journal

View full text Add to dashboard Cite

KDM3A/Ets1 epigenetic axis contributes to PAX3/FOXO1‐driven and independent disease‐promoting gene expression in fusion‐positive Rhabdomyosarcoma

Abstract: Abbreviations shRNA, short hairpin ribonucleic acid; qRT-PCR, quantitative reverse transcription-polymerase chain reaction; IVIS, in vivo imaging system; KD, knock down.

Cited by 5 publications

References 53 publications

ets1 associates with KMT5A to participate in high glucose-mediated EndMT via upregulation of PFN2 expression in diabetic nephropathy

ets1 associates with KMT5A to participate in high glucose-mediated EndMT via upregulation of PFN2 expression in diabetic nephropathy

Lysine demethylase 5A promotes prostate adenocarcinoma progression by suppressing microRNA-330-3p expression and activating the COPB2/PI3K/AKT axis in an ETS1-dependent manner

RGL2 as an age-dependent factor regulates colon cancer progression

Contact Info

Product

Resources

About