Project Grant R01CA285684

A NOVEL ROLE FOR EZH2 IN PARP REGULATION AND PARPI-RESISTANCE IN PROSTATE CANCER - PROSTATE CANCER IS THE LEADING CAUSE OF CANCER-RELATED DEATHS IN AMERICAN MEN. IT IS ESTIMATED THAT EACH YEAR MORE THAN 180,000 NEW PROSTATE CANCER PATIENTS WILL BE DIAGNOSED, AND APPROXIMATELY 26,000 PATIENTS IN THE UNITED STATES WILL DIE, PRIMARILY DUE TO METASTASIS. THIS OCCURS DESPITE ADVANCES IN EARLY DETECTION AND TREATMENT. THE AVAILABLE TREATMENT OPTIONS ARE LIMITED, NOT VERY EFFECTIVE, AND ASSOCIATED WITH SEVERE SIDE EFFECTS. FURTHERMORE, PROSTATE CANCER PATIENTS CAN DEVELOP RESISTANCE TO THE CURRENTLY AVAILABLE THERAPEUTICS. THEREFORE, THIS PROPOSAL WILL HELP DEVELOP EFFECTIVE TREATMENTS AND ADDRESS MECHANISMS OF THERAPEUTIC RESISTANCE FOR MEN WITH METASTATIC PROSTATE CANCER. ENHANCER OF ZEST HOMOLOG 2 (EZH2) SPECIFICALLY MODIFIES THE HISTONE H3 PROTEIN AT ITS LYSINE 27; THEREBY, TIGHTLY WINDING DNA AND SILENCING GENE EXPRESSION. OUR PREVIOUS WORK SHOWED THAT EZH2 IS UPREGULATED IN ADVANCED PROSTATE CARCINOMAS AND METASTATIC PROSTATE CANCER, AND PROSTATE CANCER PATIENTS WHO HAVE HIGHER EXPRESSION LEVELS OF EZH2 HAVE SHORTER SURVIVAL TIMES THAN PROSTATE CANCER PATIENTS WITH LOW OR NO EXPRESSION OF EZH2. WE ALSO FOUND THAT HIGH EXPRESSION LEVELS OF EZH2 INDUCE CHROMOSOME INSTABILITY BY REPRESSING MANY IMPORTANT PROTEINS THAT ARE RESPONSIBLE FOR REPAIR OF DNA DAMAGE. DNA DAMAGE AND IMPROPER DNA REPAIR CAN LEAD TO THE INITIATION AND PROGRESSION OF MANY CANCERS, INCLUDING PROSTATE CANCER. RECENTLY, PHARMACOLOGICAL INHIBITORS OF POLY ADP-RIBOSE POLYMERASES (PARPS) HAVE BEEN CLINICALLY TESTED FOR THE TREATMENT OF PROSTATE CANCER; HOWEVER, THESE DRUGS ARE ONLY EFFECTIVE IN A SUBSET OF PATIENTS WITH DNA REPAIR DEFECTS. FURTHERMORE, PATIENTS CAN DEVELOP THERAPEUTIC RESISTANCE TO PARP INHIBITORS. THEREFORE, TREATMENT WITH PARP INHIBITORS ALONE MAY NOT BE EFFECTIVE FOR EVERY PATIENT, SUGGESTING THE IMPORTANCE OF OTHER BIOLOGICAL MECHANISMS IN REGULATING THE DEVELOPMENT AND PROGRESSION OF PROSTATE CANCER. MOST ADVANCED PROSTATE CANCER CELLS HAVE HIGHER LEVELS OF EZH2 AND PARP1 PROTEINS COMPARED TO THAT IN EARLY-STAGE PROSTATE CANCER CELLS, SUGGESTING THE IMPORTANCE OF THESE PROTEINS IN PROSTATE CANCER PROGRESSION. WE FOUND THAT EZH2 DIRECTLY INTERACTS WITH AND METHYLATES A LYSINE OF PARP1. IN THE PROPOSED PROJECT, WE WILL IDENTIFY PRECISELY HOW EZH2-MEDIATED PARP1 LYSINE METHYLATION REGULATES PARP1'S FUNCTION IN DNA DAMAGE REPAIR AND TRANSCRIPTION ACTIVITY. UNDERSTANDING THESE MECHANISMS WILL LEAD TO THE FUTURE DESIGN OF NEW INHIBITORS OF EZH2 AND PARP1. FURTHERMORE, OUR PRELIMINARY DATA STRONGLY SUGGEST THAT PARPI-RESISTANT TUMORS HAVE HIGHER LEVELS OF EZH2 COMPARED TO PARPI-SENSITIVE TUMORS, SUGGESTING EZH2 PLAYS A CRITICAL ROLE IN PARPI- RESISTANCE. THEREFORE, OUR WORK PROVIDES A NOVEL RATIONALE TO TARGET EZH2 IN PARPI-RESISTANT PCA.