Die Rolle des Chromatinmodulators CHD1 im kastrationsresistenten Prostatakarzinom

The role of the chromatin remodeling protein CHD1 in castration resistant prostate cancer

by Simon Joseph Böcker
Doctoral thesis
Date of Examination:2021-10-05
Date of issue:2021-09-02
Advisor:Prof. Dr. Steven Johnsen
Referee:Prof. Dr. Steven Johnsen
Referee:Prof. Dr. Lutz Trojan
Persistent Address: http://dx.doi.org/10.53846/goediss-8796

 

 

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Abstract

English

Current therapy of metastasized prostate cancer largely depends on androgen-deprivation therapy (ADT). Despite initial response, tumors inevitably reach castration resistance (CRPC), a stage at which chemotherapy and second-generation anti-androgens like Abiraterone and Enzalutamide represent the main remaining therapeutic options. Acquired resistance to these drugs is an emerging problem, raising a need for new approaches. Loss of Chromodomain Helicase DNA binding protein 1 (CHD1) seems to be more prevalent in CRPC compared to earlier tumor stages. In our work, we identified a correlation between androgen-independent growth and CHD1 depletion in LNCaP prostate cancer cells. Using RNA sequencing, we showed a correlation between CHD1 knockdown and upregulation of Enhancer of Zeste Homolog 2 (EZH2) which could be confirmed at protein level. Treatment with a specific EZH2 inhibitor(1 µM JQ-EZ ) showed a stronger effect on the proliferation of CHD1-depleted cells compared to controls. To further characterize this association, as well as the genome-wide binding profiles, we performed chromatin immunoprecipitation followed by high throughput sequencing (ChIP-seq) for CHD1 and EZH2 as well as for the histone modifications H3K4me3, H3K27me3 and H3K27ac in normal FBS as well as in charcoal-stripped serum (CSS). We hereby propose a newly discovered synthetic lethality which, in the future, might be exploited for treatment of prostate cancer, e.g. in patients ineligible for chemotherapeutics.
Keywords: CHD1; prostate cancer
 
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