Die Rolle der CHD1 Depletion im Prostatakarzinom bei der epithelial zu mesenchymalen Transition und der ossären Metastasierung

The role of CHD1 depletion in prostate cancer during epithelial to mesenchymal transition and osseous metastasis

by Katharina Flemming
Doctoral thesis
Date of Examination:2025-01-24
Date of issue:2025-01-17
Advisor:PD Dr. Annemarie Uhlig
Referee:Prof. Dr Arndt Schilling
Referee:Prof. Dr. Ralf Dressel
Persistent Address: http://dx.doi.org/10.53846/goediss-10965

 

 

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Abstract

English

In the treatment of advanced prostate cancer with androgen deprivation, almost all patients develop castration resistance after some time. The tumor growth continues despite ongoing therapy. In these castration-resistant tumor cells an increased depletion of the chromatin modulator CHD1 was observed. A link between CHD1 and androgen resistance can therefore be assumed. The aim of this study was to investigate the possible influence of CHD1 depletion on prostate carcinoma cells and the influence of androgen deprivation on the CHD1-depleted cells. CHD1-depleted LNCaP cells were analyzed at the protein and RNA level using various methods. A dependence of mesenchymal markers on the CHD1 depletion and on androgen deprivation was found. CHD1-depleted cells migrate more frequently and typical EMT markers are upregulated. This can already be observed in standard medium and is further enhanced in androgen deprivation. As prostate carcinoma cells often metastasize to the bone, a possible change in the tumour cells to osteotropic cells was also investigated. No change in knockdown was found here, but a clear upregulation of osteotropic markers in the CHD1-depleted cells in androgen deprivation. The results indicate that CHD1 depletion in cells is responsible for their more aggressive growth and increased metastasis. Androgen deprivation further enhances these properties, and androgen deprivation stimulates osteomimicry in the cells. It remains to be investigated how far these changes go and whether the CHD1 depleted tumor cells may begin to metastasize under androgen deprivation, which would mean that androgen deprivation would be contraindicated in patients with CHD1 depletion.
Keywords: CRPC; Osteomimicry; castrate-resistant prostate cancers; Prostate cancer; CHD1; metastasis; Androgen deprivation; EMT; epithelial to mesenchymal transition