Abstract 5458: Elevated level of Fibrillarin induces chemoresistance by interfering p53 pathway in cancers

Abstract

Abstract Fibrillarin (FBL), an rRNA 2′-O-methyltransferase, has long been recognized as the enzymatic unit of the C/D box small nucleolar ribonucleoprotein (snoRNP) involved in the first step of pre-rRNA processing. It is not until recently that the link between FBL and cancers has been unveiled. As a direct regulatory target of Myc and p53, FBL is frequently upregulated in breast cancers and prostate cancers. High expression of FBL has also been shown to be associated with poor survival in patients with breast cancer. Our recent study found that FBL overexpression contributes to tumorigenesis and confers cellular resistance to chemodrugs. However, the underlying mechanism of chemoresistance elicited by FBL upregulation is still elusive. Here, we studied the molecular roles of FBL on p53 response. The p53 pathway in response to etoposide and actinomycin D were examined in a variety cell lines including U-2OS, MCF7, H1299, ZR75-1, A549 and an FBL inducible cell line. Western blotting and immunofluorescent staining were employed to examine protein level and their cellular localization. We found that ectopic expression of FBL enhanced the protein level of MDM2, resulting in decreased p53 accumulation and activity in response to chemodrugs. Interestingly, MDM2 was partially recruited to the nucleoli under stimuli. FBL depletion abrogated the nucleolar recruitment of MDM2 and subsequently dampened p53 activation. In conclusion, physiological level of FBL sequesters and stabilizes MDM2 in the nucleoli, therefore inhibits p53 degradation. When upregulated in cancers, FBL stabilizes nucleus MDM2 and promotes the degradation of p53 Citation Format: Teng Xu, Suthakar Ganapathy, Meijun Long, Chul Ha, Zhi-Min Yuan, Hang Su. Elevated level of Fibrillarin induces chemoresistance by interfering p53 pathway in cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5458. doi:10.1158/1538-7445.AM2015-5458