title: Elevated snoRNA biogenesis is essential in breast cancer.
abstract: Hyperactive ribosomal biogenesis is widely observed in cancer, which has been partly attributed to the increased rDNA transcription by Pol I in cancer. However, whether small nucleolar RNAs (snoRNAs), a class of non-coding RNAs crucial in ribosomal RNA (rRNA) maturation and functionality, are involved in cancer remains elusive. We report that snoRNAs and fibrillarin (FBL, an enzymatic small nucleolar ribonucleoprotein, snoRNP) are frequently overexpressed in both murine and human breast cancer as well as in prostate cancers, and significantly, that this overexpression is essential for tumorigenicity in vitro and in vivo. We demonstrate that when the elevated snoRNA pathway is suppressed, the tumor suppressor p53 can act as a sentinel of snoRNP perturbation, the activation of which mediates the growth inhibitory effect. On the other hand, high level of FBL interferes with the activation of p53 by stress. We further show that p53 activation by FBL knockdown is not only regulated by the ribosomal protein-MDM2-mediated protein stabilization pathway, but also by enhanced PTB-dependent, cap-independent translation. Together, our data uncover an essential role of deregulated snoRNA biogenesis in tumors and a new mechanism of nucleolar modulation of p53.
authors.affiliation: Department of Radiation Oncology, University of Texas Health Science Center at San Antonio, TX, USA.
authors.forename: H
authors.initials: H
authors.lastname: Su
authors.affiliation: Department of Radiation Oncology, University of Texas Health Science Center at San Antonio, TX, USA.
authors.forename: T
authors.initials: T
authors.lastname: Xu
authors.affiliation: 1] Department of Radiation Oncology, University of Texas Health Science Center at San Antonio, TX, USA [2] Department of Genetics and Complex Diseases, Harvard University, Boston, MA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Ganapathy
authors.affiliation: Department of Radiation Oncology, University of Texas Health Science Center at San Antonio, TX, USA.
authors.forename: M
authors.initials: M
authors.lastname: Shadfan
authors.affiliation: 1] Department of Radiation Oncology, University of Texas Health Science Center at San Antonio, TX, USA [2] Department of Genetics and Complex Diseases, Harvard University, Boston, MA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Long
authors.affiliation: Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, TX, USA.
authors.forename: T H-M
authors.initials: TH
authors.lastname: Huang
authors.affiliation: Department of Urology, University of Texas Health Science Center at San Antonio, TX, USA.
authors.forename: I
authors.initials: I
authors.lastname: Thompson
authors.affiliation: 1] Department of Radiation Oncology, University of Texas Health Science Center at San Antonio, TX, USA [2] Department of Genetics and Complex Diseases, Harvard University, Boston, MA, USA.
authors.forename: Z-M
authors.initials: ZM
authors.lastname: Yuan
mesh_terms: D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics*; D002453:Cell Cycle; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics; D005260:Female; D006801:Humans; D016133:Polymerase Chain Reaction; D020537:RNA, Small Nucleolar / Q000096:biosynthesis*
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D020537:RNA, Small Nucleolar; C047458:fibrillarin