Nuclear ErbB2 Enhances Translation and Cell Growth by Activating Transcription of Ribosomal RNA Genes

Li, Long-yuan; Chen, Hsiuyi; Hsieh, Yi‐Hsien; Wang, Ying-Nai; Chu, Hsiao Ju; Chen, Ya Huey; Chen, Hui-Yu; Chien, Peng-Ju; Tzong, Haou; Tsai, Ho Cheng; Lai, Chien‐Chen; Sher, Yuh Pyng; Lien, Han‐Chung; Tsai, Chang Hai; Hung, Mien‐Chie

doi:10.1158/0008-5472.can-10-3504

Cited by 66 publications

(66 citation statements)

References 40 publications

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“…Increased ribosome production coupled to elevated protein translation facilitates cell growth and proliferation, and crucially contributes to tumor progression (19,42). Studies have demonstrated that elevated rRNA synthesis is closely associated with cell transformation and cell proliferation, and a few rRNAs are overexpressed in cancers, such as prostate cancer, gastric cancer, and breast cancer (22,37).…”

Section: Discussionmentioning

confidence: 99%

“…Ribosomal biogenesis and protein synthesis fundamentally determine cell growth (19,41,42). Cell growth was remarkably restrained by approximately 25% in MDA-MB-231 cells with HSPC111 knockdown characterized by cell number counting and the MTT assay, compared with the parental control and scrambled control (P < 0.05, Fig.…”

Section: Attenuated Protein Synthesis Upon Hspc111 and Rtcd1 Reductionmentioning

confidence: 95%

“…Elevated rRNA concentrations are commonly seen in human cancers associated with enhanced protein synthesis and accelerated cell proliferation (19,39). For example, increased rRNA transcription and ribosomal biogenesis were observed in cancers subject to c-Myc activation (17,18).…”

Section: Attenuated Protein Synthesis Upon Hspc111 and Rtcd1 Reductionmentioning

confidence: 99%

“…Enhanced rRNA synthesis and ribosomal biogenesis are commonly seen in human cancers coupled with resultant protein translation and cell-proliferation acceleration (17)(18)(19). The effect of c-Myc on driving cell growth is in part due to its role in transcribing rDNA and advancing ribosomal biogenesis (20).…”

Section: Introductionmentioning

confidence: 99%

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HSPC111 Governs Breast Cancer Growth by Regulating Ribosomal Biogenesis

Zhang

Yin

Wang

et al. 2014

Molecular Cancer Research

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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,

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Section: Discussionmentioning

confidence: 99%

Section: Attenuated Protein Synthesis Upon Hspc111 and Rtcd1 Reductionmentioning

confidence: 95%

Section: Attenuated Protein Synthesis Upon Hspc111 and Rtcd1 Reductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

HSPC111 Governs Breast Cancer Growth by Regulating Ribosomal Biogenesis

Zhang

Yin

Wang

et al. 2014

Molecular Cancer Research

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“…We have come a long way since the days when the notion of ErbBs in the nucleus was so utterly challenging that it was regarded as either 'ridiculous or sublime' (Waugh & Hsuan 2001). Indeed, compelling evidence has shown ErbB-2 localization in the nucleus of BC cells, where it functions as a transcriptional regulator (Tan et al 2002, Wang et al 2004, Kim et al 2009, Beguelin et al 2010, Li et al 2011, Diaz Flaque et al 2013a,b, Cordo Russo et al 2015. However, the role of nuclear ErbB-2 (NErbB-2) as a biomarker and a target of therapy in BC is still unexplored.…”

Section: Introductionmentioning

confidence: 99%

ErbB-2 nuclear function in breast cancer growth, metastasis and resistance to therapy

Elizalde¹,

Russo²,

Chervo³

et al. 2016

Endocrine-Related Cancer

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Approximately 15-20% of breast cancers (BC) show either membrane overexpression of ErbB-2 (MErbB-2), a member of the ErbBs family of receptor tyrosine kinases, or ERBB2 gene amplification. Until the development of MErbB-2-targeted therapies, this BC subtype, called ErbB-2-positive, was associated with increased metastatic potential and poor prognosis. Although these therapies have significantly improved overall survival and cure rates, resistance to available drugs is still a major clinical issue. In its classical mechanism, MErbB-2 activates downstream signaling cascades, which transduce its effects in BC. The fact that ErbB-2 is also present in the nucleus of BC cells was discovered over twenty years ago. Also, compelling evidence revealed a non-canonical function of nuclear ErbB-2 as a transcriptional regulator. As a deeper understanding of nuclear ErbB-2 actions would be crucial to the disclosure of its role as a biomarker and a target of therapy in BC, we will here review its function in BC, in particular, its role in growth, metastatic spreading and response to currently available MErbB-2-positive BC therapies.

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ERBB2b mRNA isoform encodes a nuclear variant of the ERBB2 oncogene in breast cancer

Hua

Bergon

Cauchy

et al. 2020

J of Cellular Biochemistry

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The presence of nuclear ERBB2 receptor-type tyrosine kinase is one of the causes of the resistance to membrane ERBB2-targeted therapy in breast cancers. It has been previously reported that this nuclear location arises through at least two different mechanisms: proteolytic shedding of the extracellular domain of the full-length receptor and translation of the messenger RNA (mRNA)-encoding ERBB2 from internal initiation codons. Here, we report a new mechanism and function where a significant portion of nuclear ERBB2 results from the translation of the variant ERBB2 mRNA under the transcriptional control of a distal promoter that is actively used in breast cancer cells. We show that both membrane ERBB2a and nuclear ERBB2b isoforms are prevalently expressed in breast cancer cell lines and carcinoma samples. The ERBB2b isoform, which is translated from mRNA variant 2, can directly translocate into the nucleus due to the lack of the signal peptide which is required for an intermediate membrane location. Small interfering RNAmediated gene silencing showed that ERBB2b can repress ERBB2a expression, encoded by variant 1, whereas ERBB2a activates ERBB2b. Nuclear ERBB2 binding to its own promoter was revealed by chromatin immunoprecipitation assay. Altogether, our results provide new insights into the origin and function of nuclear ERBB2 where it can participate at the same time in a positive or a negative feedback autoregulatory loop, dependent on which of its promoters this bona fide transcription factor is acting. They also provide a new understanding for the resistance to therapies targeting the membrane-anchored ERBB2 in breast cancer.

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Nuclear ErbB2 Enhances Translation and Cell Growth by Activating Transcription of Ribosomal RNA Genes

Cited by 66 publications

References 40 publications

HSPC111 Governs Breast Cancer Growth by Regulating Ribosomal Biogenesis

HSPC111 Governs Breast Cancer Growth by Regulating Ribosomal Biogenesis

ErbB-2 nuclear function in breast cancer growth, metastasis and resistance to therapy

ERBB2b mRNA isoform encodes a nuclear variant of the ERBB2 oncogene in breast cancer

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