HSPC111 Governs Breast Cancer Growth by Regulating Ribosomal Biogenesis

Changwen Zhang,Juan Ma,Sijin Liu,Shuping Zhang,Chunyang Yin,Lei Wang,Zhihong Zhang,Yi Qian,Yong Xu

doi:10.1158/1541-7786.mcr-13-0168

Changwen Zhang, Juan Ma + Show 7 more

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https://doi.org/10.1158/1541-7786.mcr-13-0168

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Abstract

Activation of c-Myc plays a decisive role in the development of many human cancers. As a transcription factor, c-Myc 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'-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. Inhibition of HSPC111-dependent ribosomal biosynthesis and protein synthesis is a promising therapeutic strategy to diminish breast cancer tumor progression.

Highlights

Breast cancer is by far the most common cancer among women and the leading cause of cancer–related deaths worldwide
We demonstrated that HSPC111 knockdown largely inhibited cell growth of MDA-MB-231 breast cancer cells in vitro and in vivo
Quantitative real-time PCR analysis Total RNAs were performed from cells using TRizol (Invitrogen), and quantitative real-time polymerase chain reaction analysis was assessed with a kit from Promega according to the manufacturer's instruction

Summary

Introduction

Breast 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 [1,2,3]. Aberrant regulation and overexpression of c-Myc are observed in most tumor types, Authors' Affiliations: 1State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing; and 2Department of Urology, Second Hospital of Tianjin Medical University, Tianjin Institute of Urology, Tianjin, China.

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