Targeting MALAT1 Augments Sensitivity to PARP Inhibition by Impairing Homologous Recombination in Prostate Cancer.
Journal
Cancer research communications
ISSN: 2767-9764
Titre abrégé: Cancer Res Commun
Pays: United States
ID NLM: 9918281580506676
Informations de publication
Date de publication:
09 10 2023
09 10 2023
Historique:
received:
18
02
2023
revised:
26
06
2023
accepted:
05
09
2023
medline:
10
10
2023
pubmed:
9
10
2023
entrez:
9
10
2023
Statut:
ppublish
Résumé
PARP 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 long noncoding RNA (lncRNA), contrives a BRCAness-like phenotype, and augments sensitivity to PARPi. Mechanistically, we show that MALAT1 silencing reprograms the homologous recombination (HR) transcriptome and makes prostate cancer cells more vulnerable to PARPi. Particularly, coinhibition 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 prostate cancer 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 patients with castration-resistant prostate cancer (CRPC), irrespective of the alterations in HR genes. PARPi are clinically approved for patients with metastatic CRPC carrying mutations in HR genes, but are ineffective for HR-proficient prostate cancer. Herein, we show that oncogenic lncRNA, MALAT1 is frequently overexpressed in advanced stage prostate cancer and plays a crucial role in maintaining genomic integrity. Importantly, we propose a novel therapeutic strategy that emphasizes MALAT1 inhibition, leading to HR dysfunction in both HR-deficient and -proficient prostate cancer, consequently augmenting their susceptibility to PARPi.
Identifiants
pubmed: 37812088
pii: 729508
doi: 10.1158/2767-9764.CRC-23-0089
pmc: PMC10561629
doi:
Substances chimiques
RNA, Long Noncoding
0
Poly(ADP-ribose) Polymerase Inhibitors
0
MicroRNAs
0
MIRN421 microRNA, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2044-2061Informations de copyright
© 2023 The Authors; Published by the American Association for Cancer Research.
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