Poly (ADP-ribose) polymerase inhibitors (PARPi) have emerged as a 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 harbour 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 BRCAness-like phenotype and demonstrates contextual synthetic lethality with PARPi. Mechanistically, we show that MALAT1silencing reprograms the HR transcriptome, thus enhancing vulnerability to PARPi. Particularly, co-inhibition of MALAT1and PARP1 exhibits a decline in clonogenic survival, delays resolution of γH2AX foci and reduces tumour burden in mice xenograft model. Moreover, we show that miR-421, a tumour-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.
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 patient's resistant to anti-androgens and conventional chemotherapeutics.
Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as a promising target of intervention for metastatic castration-resistant prostate cancer (mCRPC), as approximately one-third of mCRPC patients harbor mutations in the genes associated with the homologous recombination (HR) pathway. Nonetheless, most patients inevitably develop resistance to PARP inhibition (PARPi), due to the induction of reversion mutations in the HR pathway. These mutations restore the function of HR genes and revert to the HR-proficient stage, which in turn decreases the vulnerability of cancer cells to PARP inhibitors. Here, we report that the clinical utility of PARPi could be efficaciously extended by targeting Metastasis associated lung adenocarcinoma transcript (MALAT1), a long non-coding RNA (lncRNA) often elevated in advanced-stage prostate cancer (PCa). In support of this, we show that mCRPC patients exhibit higher expression of genes involved in HR, which positively correlate with MALAT1 levels. Furthermore, RNA interference (RNAi)-mediated depletion of MALAT1 in CRPC cells perturb the expression of key HR genes, namely BRCA1/2, RAD51, EXO1, CHEK1/2, subsequently resulting in HR deficiency. This, in turn, escalates accumulation of DNA lesions in the MALAT1 ablated cells as noticed by abundance in γH2AX, a marker for DNA damage. As a consequence, MALAT1 ablated cells instigates G1/S phase arrest to fetch additional time to repair the damaged DNA or to induce apoptosis. Furthermore, we also provide evidence that the HR deficiency induced by MALAT1 depletion phenocopies “BRCAness” and exhibits synergy with clinically approved DNA repair inhibitors such as Olaparib. In particular, co-inhibition of MALAT1 and PARP1 exhibits a significant anti-proliferative effect reduced clonogenic survival and delays the resolution of γH2AX foci in CRPC cell lines. Taken together, our results establish that MALAT1 plays a central role in regulating the DNA damage response and provides a mechanistic rationale for dual targeting of MALAT1 and PARP in mCRPC patients. Citation Format: Anjali Yadav, Tanay Biswas, Ayush Praveen, Bushra Ateeq. MALAT1 ablation dismantles homologous recombination repair machinery and sensitizes castrate resistant prostate cancer cells to PARP inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1542.
Mammalian genome has a profound effect of DNA methylation or covalent addition of a methyl group to cytosine with reference to CpG dinucleotide. These modifications are very stable but reversible. The effect of mutation of a number of Tumor suppressor gene (TSGs) can be mimicked by the change in methylation of promoter. Hypomethylation and
The emergence of subclonal mutations in high grade colorectal (CRC) tumors driving resistance against EGFR targeting is a major challenge, thus necessitating the discovery of alternative therapeutic strategies. Targeting aberrantly active WNT signaling provides an alternate route for CRC treatment. Here we show that the high DKC1 expression in CRC patients associates with advanced-stage disease regardless of RAS/RAF mutation status, indicating the potential of DKC1 as a pan-CRC therapeutic target. We show a direct regulation of DKC1 downstream of canonical WNT signaling and confirm it as one of the WNT targets. Mechanistically, DKC1 regulates several critical cellular processes such as telomere maintenance, pseudouridylation of ribosomal RNAs, ribosomal biogenesis, etc. However, its plausible association with cancer stemness remains largely unexplored. We generated stable DKC1 knockdown (DKC1-KD) cell lines, namely WiDr and Colo320HSR to investigate its role in cancer stemness and CRC progression. DKC1-KD cells show a significant reduction in the tumor sphere forming ability along with diminished cell surface expression of stemness markers. Using multiple publicly available gene expression datasets for CRC patients, we performed Gene Set Variation Analysis to characterize the association of DKC1 with upregulated gene signature of consensus molecular subtype 2 (CMS2) of CRC, which has been associated with the highest incidence rate and active WNT signaling. Further, Database for Annotation Visualization and Integrated Discovery tool-based analysis across these CRC patient samples striated based on DKC1 expression shows positive enrichment of biological processes related to cell cycle regulation. Consistently, we observed a G2/M phase cell cycle arrest upon silencing DKC1 in CRC cells. We also show that silencing DKC1 results in enhanced chemosensitivity with a remarkable reduction in lipid accumulation. Moreover, upon DKC1 silencing, an increase in epithelial marker E-cadherin and a decrease in mesenchymal marker N-cadherin expression was observed, suggesting its role in epithelial-to-mesenchymal transition (EMT) in CRC. Our findings demonstrate the role of DKC1 in regulating stemness, drug resistance, and EMT to drive CRC oncogenicity. Taken together, we highlight the role of DKC1 as the most suitable pan-CRC drug target by employing the potential of pharmacological inhibitors against WNT signaling. Citation Format: Shivansh Nigam, Ayush Praveen, Bushra Ateeq. WNT signaling-mediated DKC1 expression drives stemness associated with colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6246.
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