The cisplatin-induced lncRNA PANDAR dictates the chemoresistance of ovarian cancer via regulating SFRS2-mediated p53 phosphorylation

Hao Wang,Xiumin Shang,Meimei Liu,Ye Kuang,Jing Jiang,Beidi Wang,Lei Fang,Zongfeng Zhang,Peilin Han,Yue Li,Peiling Li

doi:10.1038/s41419-018-1148-y

Abstract

As a component of p53-dependent lncRNA (long non-coding RNA), PANDAR (the promoter of CDKN1A antisense DNA damage activated RNA) participates in the epigenetic regulation in human cancer. However, the involvement of PANDAR in cancer chemoresistance is unknown. In this study, we report that PANDAR serves as a negative regulator of cisplatin sensitivity in human ovarian cancer via PANDAR-SRFS2-p53 feedback regulation in nuclear. Our data showed that among the drugs commonly used in ovarian cancer therapy, cisplatin induces higher levels of PANDAR compared with doxorubicin and paclitaxel. We also proved that PANDAR exhibited higher expression in cisplatin-resistant ovarian cancer tissues and cells, compared with cisplatin-sensitive ones, and this expression pattern depends on wild-type p53 (wt-p53), not mutant-p53 (mt-p53). In vitro and in vivo, PANDAR overexpression improved cell survival rate and tumor growth in response to cisplatin, while depletion of PANDAR leads to a reduced tumor growth. Further investigation revealed that PANDAR-reduced cisplatin sensitivity was likely or partly due to the PANDAR-binding protein SFRS2 (arginine/serine-rich 2), a splicing factor with the ability to negative regulate p53 and its phosphorylation at Serine 15 (Ser15). This feedback regulation of PANDAR–SFRS2–p53 leads to a reduced transactivation of p53-related pro-apoptotic genes, such as PUMA (p53-upregulated modulator of apoptosis). In addition, in platinum-treated patients with relapsed ovarian cancer, resistant period was positively correlated with the expression of PANDAR and SFRS2, and inversely associated with expression of p53-Ser15 and PUMA in these clinical tissues. Last but not least, the role of PANDAR in chemoresistance was confirmed in patients with ovarian cancer. These findings reveal a novel regulatory maneuver of cancer cells in response to chemostress, and might shed light on overcoming cisplatin resistance in ovarian cancer.

Highlights

Ovarian cancer (OC) continues to kill more than 150,000 women every year worldwide[1]
To investigate whether Long non-coding RNAs (lncRNAs) PANDAR was associated with ovarian cancer chemosensitivity, we examined PANDAR expression profile in cisplatin-sensitive and cisplatin-resistant cells of OC (Fig. 1)
Data showed that wt-p53 was positive in OC cell lines except SKOV3, and wt-p53 was only seen in the cytoplasm of A2780-DDP and HO-8910PM cells (Supplementary Fig. S1a, b), indicating that PANDAR roles in ovarian cancer chemoresistance could be sought among A2780, HO-8910, HO-8910PM, and A2780-DDP cell lines

Summary

Introduction

Ovarian cancer (OC) continues to kill more than 150,000 women every year worldwide[1]. We found a matching sequence of PANDAR (167bp–176bp) containing 5′-CCAG-3′, which is reported as the high-affinity binding sequence recognized by SFRS2 and could be found in all SELEX (Systematic Evolution of Ligands by Exponential Enrichment) consensus sequences and in all identified SFRS2-specific ESEs (exon-splicing enhancers)[12] In line with these observations, we reason that whether PANDAR could interact with SFRS2 in OC cells. To fill the above gaps, we studied the role of PANDAR in cisplatin sensitivity and discovered that cisplatininduced PANDAR expression counter-regulates nuclear p53 and its phosphorylation at Ser[15] via interacting with SFRS2, which in turn, attenuates cisplatin sensitivity in ovarian cancer chemotherapy

Results

Discussion

Materials and Methods