HSPC111 Governs Breast Cancer Growth by Regulating Ribosomal Biogenesis

Abstract

Activation of c-Myc plays a decisive role in the development of many human cancers. As a transcription factor, cMyc facilitates cell growth and proliferation by directly transcribing a multitude of targets, including rRNAs and ribosome proteins. However, how to elucidate the deregulation of rRNAs and ribosome proteins driven by c-Myc in 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 RTCD1 synergistically modulated cell growth and cellular size through commanding rRNA synthesis and ribosome assembly coupled to protein production. Finally, overall survival analysis revealed that concomitant upregulation of 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. Ó2014 AACR. IntroductionBreast cancer is by far the most common cancer among women and the leading cause of cancer-related deaths worldwide. The primary tumor and metastases to distant organs often cause significant morbidity and mortality. Numerous studies suggest that the oncogene c-Myc plays a crucial role in the development and progression of breast cancer. Along with its partner protein Max, c-Myc regulates an estimated 10% to 15% of genes in the human genome, and globally reprograms cells and drives proliferation (1-3). Aberrant regulation and overexpression of c-Myc are observed in most tumor types,

Signaling activated by nucleolar localised Notch4 Intracellular Domain underlies protection from genomic damage

“…Somewhat unexpectedly we observed that NIC4 controls transcription of ribosomal pre-rRNA, implicating Notch4 in ribosome biogenesis, although the physiological consequences of this central cellular process, remains to be investigated. Together, these observations suggest an additional layer of regulation of Notch4 activity with implications for growth regulation in development and disease [40,41,42,43].…”

Casein kinase 2 inhibits HomolD‐directed transcription by Rrn7 in Schizosaccharomyces pombe

“…In metazoans such as rat, chicken, human and Caenorhabditis elegans, CK2 mRNA and protein expression and activity are particularly high in organs during the early stages of development, compared with their adult counterparts [35]. CK2 is also more active in tumor tissues that have rapid proliferation rates than in normal tissues [5,6]. Furthermore, proliferation demands an increment of protein synthesis, which correlates with an increase in ribosomal biogenesis [36] and requires extremely fine regulation of the synthesis of the required amounts of proteins and rRNAs.…”

“…The abundance of ribosomes within a cell depends upon the availability of their components; therefore, regulation of rRNA and ribosomal protein synthesis impact the status of ribosome biogenesis. Several factors can modulate rRNA synthesis through rDNA transcription, such as the cell growth rate, chromatin structure, rDNA copy number, nutritional status, growth factors and chemical stresses [1][2][3][4][5][6]. Studies in human cells have revealed that selectivity factor 1, which binds to the rDNA gene promoter and promotes recruitment of pol I [7], is regulated by casein kinase 2 (CK2), extracellular signal-regulated kinase and mTOR [8][9][10][11].…”

“…(A-C) In vitro transcription assays using S. pombe whole-cell extracts and a TATA À Inr + template, derived from the nmt1 gene, with a downstream G-less cassette. The assays were performed with 4 mM ATP in the absence or presence of increasing amounts of CK2 holoenzyme(5,10,15,20 or 25 pmol) (A), TBB (12.5, 25, or 50 lM) (B), or an anti-CK2a Ig (0.4, 1.6 or 3.2 lg) (C). Control experiments were performed with ATP and phosphorylation buffer (A; Mock), DMSO (B) or IgG (C), or none of these components (NT).…”

Selective amplification and sequencing of cyclic phosphate–containing RNAs by the cP-RNA-seq method

“…Ribozymes 11,12 and Mpn1 exonuclease 13 also form a cP-containing 3′-end in their cleaved RNA fragments. Such cP formations are not just the result of specific ribonuclease digestions, but cP formations themselves can have a functional significance: cP formations regulate RNA-protein interactions, RNA stability and turnover, and cell proliferation 7,14–16 . In tRNA splicing, 3′-terminal cP of 5′-exons is an important intermediate which is processed by a cyclic phosphodiesterase for ligation with 3′-exons 17 .…”