Rbf/E2F1 control growth and endoreplication via steroid-independent Ecdysone Receptor signalling in Drosophila prostate-like secondary cells
<p>In prostate cancer, loss of the tumour suppressor gene, <em>Retinoblastoma</em> (<em>Rb</em>), and consequent activation of transcription factor E2F1 typically occurs at a late-stage of tumour progression. It appears to regulate a switch to an andro...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
Public Library of Science
2023
|
| _version_ | 1826310774044229632 |
|---|---|
| author | Sekar, A Leiblich, A Wainwright, SM Mendes, CC Sarma, D Hellberg, JEEU Gandy, C Goberdhan, DCI Hamdy, FC Wilson, C |
| author_facet | Sekar, A Leiblich, A Wainwright, SM Mendes, CC Sarma, D Hellberg, JEEU Gandy, C Goberdhan, DCI Hamdy, FC Wilson, C |
| author_sort | Sekar, A |
| collection | OXFORD |
| description | <p>In prostate cancer, loss of the tumour suppressor gene, <em>Retinoblastoma</em> (<em>Rb</em>), and consequent activation of transcription factor E2F1 typically occurs at a late-stage of tumour progression. It appears to regulate a switch to an androgen-independent form of cancer, castration-resistant prostate cancer (CRPC), which frequently still requires androgen receptor (AR) signalling. We have previously shown that upon mating, binucleate secondary cells (SCs) of the <em>Drosophila melanogaster</em> male accessory gland (AG), which share some similarities with prostate epithelial cells, switch their growth regulation from a steroid-dependent to a steroid-independent form of Ecdysone Receptor (EcR) control. This physiological change induces genome endoreplication and allows SCs to rapidly replenish their secretory compartments, even when ecdysone levels are low because the male has not previously been exposed to females. Here, we test whether the <em>Drosophila</em> Rb homologue, Rbf, and E2F1 regulate this switch. Surprisingly, we find that excess Rbf activity reversibly suppresses binucleation in adult SCs. We also demonstrate that Rbf, E2F1 and the cell cycle regulators, Cyclin D (CycD) and Cyclin E (CycE), are key regulators of mating-dependent SC endoreplication, as well as SC growth in both virgin and mated males. Importantly, we show that the CycD/Rbf/E2F1 axis requires the EcR, but not ecdysone, to trigger CycE-dependent endoreplication and endoreplication-associated growth in SCs, mirroring changes seen in CRPC. Furthermore, Bone Morphogenetic Protein (BMP) signalling, mediated by the BMP ligand Decapentaplegic (Dpp), intersects with CycD/Rbf/E2F1 signalling to drive endoreplication in these fly cells. Overall, our work reveals a signalling switch, which permits rapid growth of SCs and increased secretion after mating, independently of previous exposure to females. The changes observed share mechanistic parallels with the pathological switch to hormone-independent AR signalling seen in CRPC, suggesting that the latter may reflect the dysregulation of a currently unidentified physiological process.</p> |
| first_indexed | 2024-03-07T07:58:29Z |
| format | Journal article |
| id | oxford-uuid:0ec0e1e9-23f5-462e-bf53-8f8f3906e9bb |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:58:29Z |
| publishDate | 2023 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | oxford-uuid:0ec0e1e9-23f5-462e-bf53-8f8f3906e9bb2023-09-06T14:26:13ZRbf/E2F1 control growth and endoreplication via steroid-independent Ecdysone Receptor signalling in Drosophila prostate-like secondary cellsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:0ec0e1e9-23f5-462e-bf53-8f8f3906e9bbEnglishSymplectic ElementsPublic Library of Science2023Sekar, ALeiblich, AWainwright, SMMendes, CCSarma, DHellberg, JEEUGandy, CGoberdhan, DCIHamdy, FCWilson, C<p>In prostate cancer, loss of the tumour suppressor gene, <em>Retinoblastoma</em> (<em>Rb</em>), and consequent activation of transcription factor E2F1 typically occurs at a late-stage of tumour progression. It appears to regulate a switch to an androgen-independent form of cancer, castration-resistant prostate cancer (CRPC), which frequently still requires androgen receptor (AR) signalling. We have previously shown that upon mating, binucleate secondary cells (SCs) of the <em>Drosophila melanogaster</em> male accessory gland (AG), which share some similarities with prostate epithelial cells, switch their growth regulation from a steroid-dependent to a steroid-independent form of Ecdysone Receptor (EcR) control. This physiological change induces genome endoreplication and allows SCs to rapidly replenish their secretory compartments, even when ecdysone levels are low because the male has not previously been exposed to females. Here, we test whether the <em>Drosophila</em> Rb homologue, Rbf, and E2F1 regulate this switch. Surprisingly, we find that excess Rbf activity reversibly suppresses binucleation in adult SCs. We also demonstrate that Rbf, E2F1 and the cell cycle regulators, Cyclin D (CycD) and Cyclin E (CycE), are key regulators of mating-dependent SC endoreplication, as well as SC growth in both virgin and mated males. Importantly, we show that the CycD/Rbf/E2F1 axis requires the EcR, but not ecdysone, to trigger CycE-dependent endoreplication and endoreplication-associated growth in SCs, mirroring changes seen in CRPC. Furthermore, Bone Morphogenetic Protein (BMP) signalling, mediated by the BMP ligand Decapentaplegic (Dpp), intersects with CycD/Rbf/E2F1 signalling to drive endoreplication in these fly cells. Overall, our work reveals a signalling switch, which permits rapid growth of SCs and increased secretion after mating, independently of previous exposure to females. The changes observed share mechanistic parallels with the pathological switch to hormone-independent AR signalling seen in CRPC, suggesting that the latter may reflect the dysregulation of a currently unidentified physiological process.</p> |
| spellingShingle | Sekar, A Leiblich, A Wainwright, SM Mendes, CC Sarma, D Hellberg, JEEU Gandy, C Goberdhan, DCI Hamdy, FC Wilson, C Rbf/E2F1 control growth and endoreplication via steroid-independent Ecdysone Receptor signalling in Drosophila prostate-like secondary cells |
| title | Rbf/E2F1 control growth and endoreplication via steroid-independent Ecdysone Receptor signalling in Drosophila prostate-like secondary cells |
| title_full | Rbf/E2F1 control growth and endoreplication via steroid-independent Ecdysone Receptor signalling in Drosophila prostate-like secondary cells |
| title_fullStr | Rbf/E2F1 control growth and endoreplication via steroid-independent Ecdysone Receptor signalling in Drosophila prostate-like secondary cells |
| title_full_unstemmed | Rbf/E2F1 control growth and endoreplication via steroid-independent Ecdysone Receptor signalling in Drosophila prostate-like secondary cells |
| title_short | Rbf/E2F1 control growth and endoreplication via steroid-independent Ecdysone Receptor signalling in Drosophila prostate-like secondary cells |
| title_sort | rbf e2f1 control growth and endoreplication via steroid independent ecdysone receptor signalling in drosophila prostate like secondary cells |
| work_keys_str_mv | AT sekara rbfe2f1controlgrowthandendoreplicationviasteroidindependentecdysonereceptorsignallingindrosophilaprostatelikesecondarycells AT leiblicha rbfe2f1controlgrowthandendoreplicationviasteroidindependentecdysonereceptorsignallingindrosophilaprostatelikesecondarycells AT wainwrightsm rbfe2f1controlgrowthandendoreplicationviasteroidindependentecdysonereceptorsignallingindrosophilaprostatelikesecondarycells AT mendescc rbfe2f1controlgrowthandendoreplicationviasteroidindependentecdysonereceptorsignallingindrosophilaprostatelikesecondarycells AT sarmad rbfe2f1controlgrowthandendoreplicationviasteroidindependentecdysonereceptorsignallingindrosophilaprostatelikesecondarycells AT hellbergjeeu rbfe2f1controlgrowthandendoreplicationviasteroidindependentecdysonereceptorsignallingindrosophilaprostatelikesecondarycells AT gandyc rbfe2f1controlgrowthandendoreplicationviasteroidindependentecdysonereceptorsignallingindrosophilaprostatelikesecondarycells AT goberdhandci rbfe2f1controlgrowthandendoreplicationviasteroidindependentecdysonereceptorsignallingindrosophilaprostatelikesecondarycells AT hamdyfc rbfe2f1controlgrowthandendoreplicationviasteroidindependentecdysonereceptorsignallingindrosophilaprostatelikesecondarycells AT wilsonc rbfe2f1controlgrowthandendoreplicationviasteroidindependentecdysonereceptorsignallingindrosophilaprostatelikesecondarycells |