Skip to main content

Advertisement

SpringerLink
Log in

Histone Deacetylase Sirtuin 2 Enhances Viability of Trophoblasts Through p65-Mediated MicroRNA-146a/ACKR2 Axis

  • Pregnancy: Original Article
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

Reduced activity of trophoblast cells is well-recognized to lead to preeclampsia (PE) progression. This study aims to evaluate the roles of histone deacetylase sirtuin 2 (SIRT2) in activity of trophoblast cells and the molecules involved. Differentially expressed genes in placental tissues between PE patients and healthy individuals were screened using microarray analyses. SIRT2 and atypical chemokine receptor 2 (ACKR2) were downregulated while miR-146a was upregulated in PE patients. SIRT2 was localized in placental syncytiotrophoblasts. Upregulation of SIRT2 enhanced viability, migration and invasion, while reduced apoptosis of HTR-8/SVneo cells. SIRT2 was found to trigger p65 deacetylation level and suppress miR-146a expression according to the luciferase and ChIP assays, whereas miR-146a was found to target ACKR2. Downregulation of p65 promoted migration and invasion of cells. Overexpression of miR-146a inhibited cell viability and blocked the function of SIRT2. ACKR2 was downregulated in tissues from PE women and its upregulation blocked the role of miR-146a. To conclude, SIRT2 promotes p65 deacetylation to suppress miR-146a expression and upregulates ACKR2 expression, therefore enhancing proliferation, migration, and invasion of HTR-8/SVneo cells. This study may offer novel thoughts into the management of PE.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Huppertz B. Traditional and new routes of trophoblast invasion and their implications for pregnancy diseases. Int J Mol Sci. 2019;21(1):289.

    Article  Google Scholar 

  2. Lala PK, Nandi P. Mechanisms of trophoblast migration, endometrial angiogenesis in preeclampsia: the role of decorin. Cell Adhes Migr. 2016;10(1–2):111–25.

    Article  CAS  Google Scholar 

  3. Lyall F, Robson SC, Bulmer JN. Spiral artery remodeling and trophoblast invasion in preeclampsia and fetal growth restriction: relationship to clinical outcome. Hypertension. 2013;62(6):1046–54.

    Article  CAS  Google Scholar 

  4. Cierna Z, Varga I, Danihel L Jr, Kuracinova K, Janegova A, Danihel L. Intermediate trophoblast--a distinctive, unique and often unrecognized population of trophoblastic cells. Ann Anat. 2016;204:45–50.

    Article  Google Scholar 

  5. Huppertz B. The critical role of abnormal trophoblast development in the etiology of preeclampsia. Curr Pharm Biotechnol. 2018;19(10):771–80.

    Article  CAS  Google Scholar 

  6. Sang C, Wang S, Zhang Z, Lu J. Characteristics and outcome of severe preeclampsia/eclampsia concurrent with or complicated by acute pancreatitis: a report of five cases and literature review. J Matern Fetal Neonatal Med. 2019;32(4):633–40.

    Article  Google Scholar 

  7. Staff AC. The two-stage placental model of preeclampsia: an update. J Reprod Immunol. 2019;134–135:1–10.

    Article  Google Scholar 

  8. Rana S, Lemoine E, Granger JP, Karumanchi SA. Preeclampsia: pathophysiology, challenges, and perspectives. Circ Res. 2019;124(7):1094–112.

    Article  CAS  Google Scholar 

  9. Haigis MC, Sinclair DA. Mammalian sirtuins: biological insights and disease relevance. Annu Rev Pathol. 2010;5:253–95.

    Article  CAS  Google Scholar 

  10. Michan S, Sinclair D. Sirtuins in mammals: insights into their biological function. Biochem J. 2007;404(1):1–13.

    Article  CAS  Google Scholar 

  11. Yang T, Sauve AA. NAD metabolism and sirtuins: metabolic regulation of protein deacetylation in stress and toxicity. AAPS J. 2006;8(4):E632–43.

    Article  Google Scholar 

  12. Lappas M, Mitton A, Lim R, Barker G, Riley C, Permezel M. SIRT1 is a novel regulator of key pathways of human labor. Biol Reprod. 2011;84(1):167–78.

    Article  CAS  Google Scholar 

  13. Hannan NJ, Beard S, Binder NK, Onda K, Kaitu'u-Lino T'J, Chen Q, et al. Key players of the necroptosis pathway RIPK1 and SIRT2 are altered in placenta from preeclampsia and fetal growth restriction. Placenta. 2017;51:1–9.

    Article  CAS  Google Scholar 

  14. Li Y, Dai D, Lu Q, Fei M, Li M, Wu X. Sirt2 suppresses glioma cell growth through targeting NF-kappaB-miR-21 axis. Biochem Biophys Res Commun. 2013;441(3):661–7.

    Article  CAS  Google Scholar 

  15. Pais TF, Szego EM, Marques O, et al. The NAD-dependent deacetylase sirtuin 2 is a suppressor of microglial activation and brain inflammation. EMBO J. 2013;32(19):2603–16.

    Article  CAS  Google Scholar 

  16. Arthurs AL, Lumbers ER, Pringle KG. MicroRNA mimics that target the placental renin-angiotensin system inhibit trophoblast proliferation. Mol Hum Reprod. 2019;25(4):218–27.

    Article  CAS  Google Scholar 

  17. Pacifico F, Lepore A, Mellone S, Sanguigno L, Federico G, Greco A, et al. The chemokine scavenging receptor D6/ACKR2 is a target of miR-146a in thyroid cancer. Genes Cancer. 2017;8(5–6):577–88.

    Article  CAS  Google Scholar 

  18. Tian S, Yu J, Zhang Y, Bian Y, Ma J, Yan J. Overexpression of PTEN regulated by miR-19b and miR-494 in the villous of recurrent spontaneous abortion patients. J Reprod Immunol. 2020;140:103133.

    Article  CAS  Google Scholar 

  19. Yan S, Cui S, Zhang L, Yang B, Yuan Y, Lv X, et al. Expression of ACKR2 in placentas from different types of preeclampsia. Placenta. 2020;90:121–7.

    Article  CAS  Google Scholar 

  20. Ayuk SM, Abrahamse H, Houreld NN. The role of photobiomodulation on gene expression of cell adhesion molecules in diabetic wounded fibroblasts in vitro. J Photochem Photobiol B. 2016;161:368–74.

    Article  CAS  Google Scholar 

  21. Ning H, Albersen M, Lin G, Lue TF, Lin CS. Effects of EdU labeling on mesenchymal stem cells. Cytotherapy. 2013;15(1):57–63.

    Article  CAS  Google Scholar 

  22. Diaz D, Prieto A, Reyes E, Barcenilla H, Monserrat J, Alvarez-Mon M. Flow cytometry enumeration of apoptotic cancer cells by apoptotic rate. Methods Mol Biol. 2015;1219:11–20.

    Article  CAS  Google Scholar 

  23. Ahmed A, Rezai H, Broadway-Stringer S. Evidence-based revised view of the pathophysiology of preeclampsia. Adv Exp Med Biol. 2017;956:355–74.

    Article  Google Scholar 

  24. Li Q, Zhang J, Su DM, et al. lncRNA TUG1 modulates proliferation, apoptosis, invasion, and angiogenesis via targeting miR-29b in trophoblast cells. Hum Genomics. 2019;13(1):50.

    Article  Google Scholar 

  25. Shan N, Zhang X, Xiao X, Zhang H, Tong C, Luo X, et al. Laminin alpha4 (LAMA4) expression promotes trophoblast cell invasion, migration, and angiogenesis, and is lowered in preeclamptic placentas. Placenta. 2015;36(8):809–20.

    Article  CAS  Google Scholar 

  26. Wang Y, Yang J, Hong T, Chen X, Cui L. SIRT2: controversy and multiple roles in disease and physiology. Ageing Res Rev. 2019;55:100961.

    Article  CAS  Google Scholar 

  27. Harting K, Knoll B. SIRT2-mediated protein deacetylation: an emerging key regulator in brain physiology and pathology. Eur J Cell Biol. 2010;89(2–3):262–9.

    Article  CAS  Google Scholar 

  28. Rothgiesser KM, Erener S, Waibel S, Luscher B, Hottiger MO. SIRT2 regulates NF-kappaB dependent gene expression through deacetylation of p65 Lys310. J Cell Sci. 2010;123(Pt 24):4251–8.

    Article  CAS  Google Scholar 

  29. Yuan F, Xu ZM, Lu LY, Nie H, Ding J, Ying WH, et al. SIRT2 inhibition exacerbates neuroinflammation and blood-brain barrier disruption in experimental traumatic brain injury by enhancing NF-kappaB p65 acetylation and activation. J Neurochem. 2016;136(3):581–93.

    Article  CAS  Google Scholar 

  30. Xiao C, Rui Y, Zhou S, Huang Y, Wei Y, Wang Z. TNF-related apoptosis-inducing ligand (TRAIL) promotes trophoblast cell invasion via miR-146a-EGFR/CXCR4 axis: a novel mechanism for preeclampsia? Placenta. 2020;93:8–16.

    Article  CAS  Google Scholar 

  31. Teoh PJ, Menzies FM, Hansell CA, et al. Atypical chemokine receptor ACKR2 mediates chemokine scavenging by primary human trophoblasts and can regulate fetal growth, placental structure, and neonatal mortality in mice. J Immunol. 2014;193(10):5218–28.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Obstetrics, Zibo Maternal and Child Health Hospital, Zibo, 255000, Shandong, People’s Republic of China

    Yingchun Yu

  2. Department of Neurology, Jinan No.7 People’s Hospital, Jinan, 251400, Shandong, People’s Republic of China

    Xiaoqin An

  3. Department of Obstetrics, Qingdao Women and Children’s Hospital, No. 6, Tongfu Road, Shibei District, Qingdao, 266034, Shandong, People’s Republic of China

    Dongmei Fan

Authors
  1. Yingchun Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaoqin An
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dongmei Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dongmei Fan.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Consents

This research was carried out with the approval and supervision of the Ethics Committee of

Zibo Maternal and Child Health Hospital and in line with the guidelines in Declaration of Helsinki.

Written confirmed consent was acquired from each respondent.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yu, Y., An, X. & Fan, D. Histone Deacetylase Sirtuin 2 Enhances Viability of Trophoblasts Through p65-Mediated MicroRNA-146a/ACKR2 Axis. Reprod. Sci. 28, 1370–1381 (2021). https://doi.org/10.1007/s43032-020-00398-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s43032-020-00398-x

Keywords

Search

Navigation