Prohibitin Links Cell Cycle, Motility and Invasion in Prostate Cancer Cells

Koushyar, S., Uysal Onganer, P., Jiang, W.G. and Dart , D.A. 2023. Prohibitin Links Cell Cycle, Motility and Invasion in Prostate Cancer Cells. International Journal of Molecular Sciences. 24 (12) 9919. https://doi.org/10.3390/ijms24129919

TitleProhibitin Links Cell Cycle, Motility and Invasion in Prostate Cancer Cells
TypeJournal article
AuthorsKoushyar, S., Uysal Onganer, P., Jiang, W.G. and Dart , D.A.
Abstract

Prohibitin (PHB) is a tumour suppressor gene with several different molecular activities. PHB overexpression leads to G1/S-phase cell cycle arrest, and PHB represses the androgen receptor (AR) in prostate cancer cells. PHB interacts with and represses members of the E2F family in a manner that may also be AR-linked, therefore making the AR:PHB:E2F interaction axis highly complex. PHB siRNA increased the growth and metastatic potential of LNCaP mouse xenografts in vivo. Conversely, PHB ectopic cDNA overexpression affected several hundred genes in LNCaP cells. Furthermore, gene ontology analysis showed that in addition to cell cycle regulation, several members of the WNT family were significantly downregulated (WNT7B, WNT9A and WNT10B), as well as pathways for cell adhesion. Online GEO data studies showed PHB expression to be decreased in clinical cases of metastatic prostate cancer, and to be correlated with higher WNT expression in metastasis. PHB overexpression reduced prostate cancer cell migration and motility in wound-healing assays, reduced cell invasion through a Matrigel layer and reduced cellular attachment. In LNCaP cells, WNT7B, WNT9A and WNT10B expression were also upregulated by androgen treatment and downregulated by androgen antagonism, indicating a role for AR in the control of these WNT genes. However, these WNTs were strongly cell cycle regulated. E2F1 cDNA ectopic expression and PHB siRNA (both cell cycle promoting effects) increased WNT7B, WNT9A and WNT10B expression, and these genes were also upregulated as cells were released from G1 to S phase synchronisation, indicating further cell cycle regulation. Therefore, the repressive effects of PHB may inhibit AR, E2F and WNT expression and its loss may increase metastatic potential in human prostate cancer.

Keywordsprostate cancer
WNT signalling
PHB
Article number9919
JournalInternational Journal of Molecular Sciences
Journal citation24 (12)
ISSN1422-0067
Year2023
PublisherMDPI
Publisher's version
License
CC BY 4.0
File Access Level
Open (open metadata and files)
Digital Object Identifier (DOI)https://doi.org/10.3390/ijms24129919
PubMed ID37373067
Web address (URL)https://www.mdpi.com/1422-0067/24/12/9919
Publication dates
Published08 Jun 2023

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