Characterisation of oncogenic pathways driving the pathogenesis of prostate cancer

Stably overexpressing TBX2 PCa cells had no alteration in proliferation rate but increased migration and invasion. Depletion of TBX2 via siRNA causes inverse effects in PC3 cells, with upregulation of CST6, NDRG1 and p21WAF1, reducing viability and migration. TBX2 shRNA stable lines were also successfully generated with results mirroring siRNA depletion.

Ch-IP qPCR assays confirmed TBX2 binds the promoters of CST6, E-cadherin, NDRG1 and p21WAF1 in PC3 cells.<br><br>Co-immunoprecipitation demonstrated that TBX2 interacts with CoREST complex members LSD1 and ZNF217 and ChIP qPCR confirmed TBX2 shRNA reduced ZNF217 recruitment to E-cadherin and NDRG1 promoters. In accordance, targeting the LSD1/ZNF217 interaction via an allosteric LSD1 inhibitor phenocopied TBX2 knockdown in PCa cells.

Effects of LSD1 inhibition, via SP2509, was demethylase independent and initiated a senescence phenotype in both C42B and PC3 cells. Indicating that TBX2 recruits the CoREST complex rather than direct repression to enact a repressive gene network in PCa to bypass senescence and enable EMT. Individual or combination inhibition of CoREST complex members attenuates TBX2 function and has exciting potential for the improved treatment of PCa.<br><br>