Abstract
Poly (ADP-ribose) polymerase inhibitors (PARPi) have emerged as a promising targeted therapeutic intervention for metastatic castrate-resistant prostate cancer (mCRPC). However, the clinical utility of PARPi is limited to a subset of patients who harbor aberrations in the genes associated with the homologous recombination (HR) pathway. Here, we report that targeting metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), an oncogenic lncRNA, contrives a BRCAness-like phenotype and augments sensitivity to PARPi. Mechanistically, we show that MALAT1 silencing reprograms the HR transcriptome and makes PCa cells more vulnerable to PARPi. Particularly, co-inhibition of MALAT1 and PARP1 exhibits a decline in clonogenic survival, delays resolution of γH2AX foci, and reduces tumor burden in mice xenograft model. Moreover, we show that miR-421, a tumor-suppressor miRNA, negatively regulates the expression of HR genes, while in aggressive PCa cases, miR-421 is sequestered by MALAT1, leading to increased expression of HR genes. Conclusively, our findings suggest that MALAT1 ablation confers sensitivity to PARPi, thus highlighting an alternative therapeutic strategy for CRPC patients, irrespective of the alterations in HR genes.
