Loss of LCMT1 and biased protein phosphatase 2A heterotrimerization drive prostate cancer progression and therapy resistance

The first line of therapy for advanced prostate cancer (PCa) is androgen-deprivation therapy (ADT) through surgical or chemical castration; however, in the majority of cases, tumors relapse in a hormone refractory or castration resistant prostate cancer (CRPC) form. Once the PCa has recurred in CRPC form, it progresses to a highly aggressive disease with frequent metastasis and poses an increased risk of morbidity and death This study shows that the loss of PP2Acα methylation in enzalutamide (Enza)-resistant CRPC cells plays a central role in imparting the resistant to the cancer cells by stabilizing the interaction of MED1, BRD4, and AR associated transcriptional complex, thereby amplifying the oncogenic AR transcriptional output through chromatin re-modulatory mechanism. Further, this study demonstrates that targeting the PP2ACα regulatory mechanisms or its downstream epigenetic effectors/mechanisms abolish the enzalutamide-resistance phenotype, thus paving the way for the development of more effective therapeutics to curtail mCRPC. The below given experiments validate the above findings. Overall design: LNCaP and VCaP enzalutamide-resistant (LNCaP-EnzaR and VCaP-EnzaR) cell line was generated by culturing their parental lines in presence of enzalutamide for 4-6 months and a comparative gene expression profiling analysis of RNA-seq data for DMSO verses ARD69 or DT061 treated LNCaP-EnzaR and VCaP-EnzaR was performed. Similar kind of comparative transcription profiling was performed for PTEN-WT verses PTEN-null mouse prostate organoids, LNCaP cells stably over-expressing LCMT1 verses LNCaP cells over-expressing LacZ, and VCaP cells verses VCaP-EnzaR cells.