HSPC111 Governs Breast Cancer Growth by Regulating

Activationofc-Mycplaysadecisiveroleinthedevelopmentofmanyhumancancers.Asatranscriptionfactor,cMyc facilitates cell growth and proliferation by directly transcribing a multitude of targets, including rRNAs and ribosomeproteins.However,howtoelucidatethederegulationofrRNAsandribosomeproteinsdrivenbyc-Mycin cancer remains a significant challenge and thus warrants close investigation. In this report, a crucial role for the HSPC111 (NOP16) multiprotein complex in governing ribosomal biogenesis and tumor growth was determined. It was discovered that enhanced HSPC111 expression paralleled the upregulation of c-Myc and was directly regulated by c-Myc in breast cancer cells. Knockdown of HSPC111 dramatically reduced the occurrence of tumorigenesis in vivo, and largely restrained tumor cell growth in vitro and in vivo. In stark contrast, HSPC111 overexpression significantly promoted tumor cell growth. Biochemically, it was demonstrated that RNA 3 0 -phosphate cyclase (RTCD1/RTCA) interacted with HSPC111, and RTCD1 was involved in the HSPC111 multiprotein complex in regulating rRNA production and ribosomal biogenesis. Moreover, HSPC111 and RTCD1synergisticallymodulatedcellgrowthandcellularsizethroughcommandingrRNAsynthesisandribosome assemblycoupledtoproteinproduction.Finally,overallsurvivalanalysisrevealedthatconcomitantupregulationof HSPC111 and RTCD1 correlated with the worst prognosis in a breast cancer cohort. Implications: Inhibition of HSPC111-dependent ribosomal biosynthesis and protein synthesis is a promising therapeutic strategy to diminish breast cancer tumor progression. Mol Cancer Res; 12(4); 583–94. � 2014 AACR.