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

作者：Hao Wang, Lei Fang, Jing Jiang, Ye Kuang, Beidi Wang, Xiumin Shang, Peilin Han, Yue Li, Meimei Liu, Zongfeng Zhang, Peiling Li · 发表于：Cell Death and Disease · 年份：2018 · DOI：10.1038/s41419-018-1148-y · 被引用次数：101 · 研究领域：Cancer-related molecular mechanisms research、RNA Research and Splicing、RNA modifications and cancer

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 ...