A Novel Splice Variant of the Inhibitor of Growth 3 Lacks the Plant Homeodomain and Regulates Epithelial–Mesenchymal Transition in Prostate Cancer Cells

Melekhova, Anna; Leeder, Mirjam; Pungsrinont, Thanakorn; Schmäche, Tim; Kallenbach, Julia; Ehsani, Marzieh; Mirzakhani, Kimia; Rasa, Seyed Mohammad Mahdi; Neri, Francesco; Baniahmad, Aria

doi:10.3390/biom11081152

Open AccessArticle

A Novel Splice Variant of the Inhibitor of Growth 3 Lacks the Plant Homeodomain and Regulates Epithelial–Mesenchymal Transition in Prostate Cancer Cells

by

Anna Melekhova

^1,†,

Mirjam Leeder

^2,†,

Thanakorn Pungsrinont

¹,

Tim Schmäche

^1,3,4,

Julia Kallenbach

¹,

Marzieh Ehsani

¹,

Kimia Mirzakhani

¹,

Seyed Mohammad Mahdi Rasa

⁵,

Francesco Neri

⁵ and

Aria Baniahmad

^1,*

¹

Institute of Human Genetics, Jena University Hospital, 07740 Jena, Germany

²

Department of Adult and Pediatric Urology, Jena University Hospital, 07743 Jena, Germany

³

Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany

⁴

National Center for Tumor Diseases (NCT/UCC), 01307 Dresden, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany

⁵

Leibniz Institute on Aging, 07745 Jena, Germany

^*

Author to whom correspondence should be addressed.

^†

These authors contributed equally to this paper.

Biomolecules 2021, 11(8), 1152; https://doi.org/10.3390/biom11081152

Submission received: 9 July 2021 / Revised: 28 July 2021 / Accepted: 29 July 2021 / Published: 4 August 2021

(This article belongs to the Special Issue 10th Anniversary of Biomolecules—Recent Advances in Understanding of Molecular Pathology and Therapeutics of Cancer)

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Abstract

Inhibitor of growth 3 (ING3) is one of five members of the ING tumour suppressor family, characterized by a highly conserved plant homeodomain (PHD) as a reader of the histone mark H3K4me3. ING3 was reported to act as a tumour suppressor in many different cancer types to regulate apoptosis. On the other hand, ING3 levels positively correlate with poor survival prognosis of prostate cancer (PCa) patients. In PCa cells, ING3 acts rather as an androgen receptor (AR) co-activator and harbours oncogenic properties in PCa. Here, we show the identification of a novel ING3 splice variant in both the human PCa cell line LNCaP and in human PCa patient specimen. The novel ING3 splice variant lacks exon 11, ING3∆ex11, which results in deletion of the PHD, providing a unique opportunity to analyse functionally the PHD of ING3 by a natural splice variant. Functionally, overexpression of ING3Δex11 induced morphological changes of LNCaP-derived 3D spheroids with generation of lumen and pore-like structures within spheroids. Since these structures are an indicator of epithelial–mesenchymal transition (EMT), key regulatory factors and markers for EMT were analysed. The data suggest that in contrast to ING3, ING3Δex11 specifically modulates the expression of key EMT-regulating upstream transcription factors and induces the expression of EMT markers, indicating that the PHD of ING3 inhibits EMT. In line with this, ING3 knockdown also induced the expression of EMT markers, confirming the impact of ING3 on EMT regulation. Further, ING3 knockdown induced cellular senescence via a pathway leading to cell cycle arrest, indicating an oncogenic role for ING3 in PCa. Thus, the data suggest that the ING3Δex11 splice variant lacking functional PHD exhibits oncogenic characteristics through triggering EMT in PCa cells.

Keywords: prostate cancer; plant homeodomain; inhibitor of growth 3

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MDPI and ACS Style

Melekhova, A.; Leeder, M.; Pungsrinont, T.; Schmäche, T.; Kallenbach, J.; Ehsani, M.; Mirzakhani, K.; Rasa, S.M.M.; Neri, F.; Baniahmad, A. A Novel Splice Variant of the Inhibitor of Growth 3 Lacks the Plant Homeodomain and Regulates Epithelial–Mesenchymal Transition in Prostate Cancer Cells. Biomolecules 2021, 11, 1152. https://doi.org/10.3390/biom11081152

AMA Style

Melekhova A, Leeder M, Pungsrinont T, Schmäche T, Kallenbach J, Ehsani M, Mirzakhani K, Rasa SMM, Neri F, Baniahmad A. A Novel Splice Variant of the Inhibitor of Growth 3 Lacks the Plant Homeodomain and Regulates Epithelial–Mesenchymal Transition in Prostate Cancer Cells. Biomolecules. 2021; 11(8):1152. https://doi.org/10.3390/biom11081152

Chicago/Turabian Style

Melekhova, Anna, Mirjam Leeder, Thanakorn Pungsrinont, Tim Schmäche, Julia Kallenbach, Marzieh Ehsani, Kimia Mirzakhani, Seyed Mohammad Mahdi Rasa, Francesco Neri, and Aria Baniahmad. 2021. "A Novel Splice Variant of the Inhibitor of Growth 3 Lacks the Plant Homeodomain and Regulates Epithelial–Mesenchymal Transition in Prostate Cancer Cells" Biomolecules 11, no. 8: 1152. https://doi.org/10.3390/biom11081152

APA Style

Melekhova, A., Leeder, M., Pungsrinont, T., Schmäche, T., Kallenbach, J., Ehsani, M., Mirzakhani, K., Rasa, S. M. M., Neri, F., & Baniahmad, A. (2021). A Novel Splice Variant of the Inhibitor of Growth 3 Lacks the Plant Homeodomain and Regulates Epithelial–Mesenchymal Transition in Prostate Cancer Cells. Biomolecules, 11(8), 1152. https://doi.org/10.3390/biom11081152

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A Novel Splice Variant of the Inhibitor of Growth 3 Lacks the Plant Homeodomain and Regulates Epithelial–Mesenchymal Transition in Prostate Cancer Cells

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