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. LNCaP enzalutamide-resistant (LNCaP-MDVR) cell line was generated by culturing the parental LNCaP cells in presence of enzalutamide for 4-6 months. The comparison of the two cell lines in terms of MED1 and AR chromatin recruitment was performed upon DMSO or ARD-69 or DT-061 treatment. LNCaP cells stably over-expressing LacZ and leucine carboxyl methyltransferase 1 (LCMT1) were prepared and used to study the differential chromatin binding of MED1 and AR.