HIF‐1α‐induced long noncoding RNA LINC02776 promotes drug resistance of ovarian cancer by increasing polyADP‐ribosylation
Abstract Background Chemoresistance remains a major hurdle in ovarian cancer (OC) treatment, as many patients eventually develop resistance to platinum‐based chemotherapy and/or PARP inhibitors (PARPi). Methods We performed transcriptome‐wide analysis by RNA sequencing (RNA‐seq) data of platinum‐res...
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| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2025-03-01
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| Series: | Clinical and Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/ctm2.70244 |
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| Summary: | Abstract Background Chemoresistance remains a major hurdle in ovarian cancer (OC) treatment, as many patients eventually develop resistance to platinum‐based chemotherapy and/or PARP inhibitors (PARPi). Methods We performed transcriptome‐wide analysis by RNA sequencing (RNA‐seq) data of platinum‐resistant and ‐sensitive OC tissues. We demonstrated the role of LINC02776 in platinum resistance in OC cells, mice models and patient‐derived organoid (PDO) models. Results We identify the long noncoding RNA LINC02776 as a critical factor of platinum resistance. Elevated expression of LINC02776 is observed in platinum‐resistant OC and serves as an independent prognostic factor for OC patients. Functionally, silencing LINC02776 reduces proliferation and DNA damage repair in OC cells, thereby enhancing sensitivity to platinum and PARPi in both xenograft mouse models and patient‐derived organoid (PDO) models with acquired chemoresistance. Mechanistically, LINC02776 binds to the catalytic domain of poly (ADP‐ribose) polymerase 1 (PARP1), promoting PARP1‐dependent polyADP‐ribosylation (PARylation) and facilitating homologous recombination (HR) restoration. Additionally, high HIF‐1α expression in platinum‐resistant tissues further stimulates LINC02776 transcription. Conclusions Our findings suggest that targeting LINC02776 represents a promising therapeutic strategy for OC patients who have developed resistance to platinum or PARPi. Key points LINC02776 promotes OC cell proliferation by regulating DNA damage and apoptosis signaling pathways. LINC02776 binds PARP1 to promote DNA damage‐triggered PARylation in OC cells. LINC02776 mediates cisplatin and olaparib resistance in OC cells by enhancing PARP1‐mediated PARylation activity and regulating the PARP1‐mediated HR pathway. The high expression of LINC02776 is induced by HIF‐1α in platinum‐resistant OC cells and tissues. |
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| ISSN: | 2001-1326 |