Targeting MALAT1 Augments Sensitivity to PARP Inhibition by Impairing Homologous Recombination in Prostate Cancer.

Poly(ADP-ribose) polymerase inhibitors (PARPi) have emerged as the most promising targeted therapeutic intervention for the treatment of metastatic castrate-resistant prostate cancer (mCRPC). However, the clinical utility of PARPi has been limited to a subset of patients who harbor aberrations in the homologous recombination (HR) pathway. Here, we report that targeting MALAT1, an oncogenic lncRNA, known to be elevated in advanced-stage prostate cancer (PCa) demonstrates contextual synthetic lethality with PARPi. We show that MALAT1 silencing reprograms the HR transcriptome, contriving BRCAness-like phenotype, thus enhancing sensitivity towards PARPi. Moreover, transcriptome profiles of mCRPC patients exhibit convergence between expression of MALAT1, HR pathway, and neuroendocrine markers. Mechanistically, we show that targeting MALAT1 leads to a decrease in EZH2, a member of polycomb repressor complex-2 (PRC2), which in turn upregulates the expression of RE1 Silencing Transcription Factor (REST), a key repressor of neuroendocrine differentiation. Overall, we showed that MALAT1 plays a pivotal role in maintaining genomic integrity, thereby promoting disease progression. Conclusively, our findings suggest that inhibiting MALAT1 confers PARPi sensitization in patients resistant to anti-androgens and conventional chemotherapeutics. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=195 SRC="FIGDIR/small/494272v1_ufig1.gif" ALT="Figure 1"> View larger version (70K): org.highwire.dtl.DTLVardef@80d842org.highwire.dtl.DTLVardef@f60793org.highwire.dtl.DTLVardef@6b81eforg.highwire.dtl.DTLVardef@1fa35d_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstract:C_FLOATNO The oncogenic lncRNA MALAT1 exhibits functional pleiotropy in PCa and promotes neuroendocrine differentiation. MALAT1 fosters PCa progression by modulating several hallmark oncogenic properties, such as malignant transformation, enhanced migratory capabilities, stemness, and ultimately contributes to drug resistance. MALAT1 enhances the transcriptional regulation of genes associated with homologous recombination thereby having a profound impact on the genome integrity in metastatic prostate cancer. Over the course of disease progression, it also promotes neuroendocrine trans-differentiation by depleting the levels of REST, the key repressor for NE transdifferentiation in prostate cancer. C_FIG