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首页> 外文期刊>Nature >SHARP1 suppresses breast cancer metastasis by promoting degradation of hypoxia-inducible factors
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SHARP1 suppresses breast cancer metastasis by promoting degradation of hypoxia-inducible factors

机译：SHARP1通过促进缺氧诱导因子的降解来抑制乳腺癌转移

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摘要

The molecular determinants of malignant cell behaviours in breast cancer remain only partially understood1. Here we show that SHARP1 (also known as BHLHE41 or DEC2) is a crucial regulator of the invasive and metastatic phenotype in triple-negative breast cancer (TNBC), one of the most aggressive types of breast cancer. SHARP 1 is regulated by the p63 metastasis suppressor and inhibits TNBC aggressiveness through inhibition of hypoxia-inducible factor la (HIF-1α) and HIF-2a (HIFs). SHARP1 opposes HIF-dependent TNBC cell migration in vitro, and invasive or metastatic behaviours in vivo. SHARP 1 is required, and sufficient, to limit expression of HIF-target genes. In primary TNBC, endogenous SHARP 1 levels are inversely correlated with those of HIF targets. Mechanistically, SHARP 1 binds to HIFs and promotes HIF proteasomal degradation by serving as the HIF-presenting factor to the proteasome. This process is independent of pVHL (von Hippel-Lindau tumour suppressor), hypoxia and the ubiquitina-tion machinery. SHARP 1 therefore determines the intrinsic instability of HIF proteins to act in parallel to, and cooperate with, oxygen levels. This work sheds light on the mechanisms and pathways by which TNBC acquires invasiveness and metastatic propensity.
机译：乳腺癌中恶性细胞行为的分子决定因素仍然只有部分了解。在这里，我们显示SHARP1（也称为BHLHE41或DEC2）是三阴性乳腺癌（TNBC）（侵袭性最强的乳腺癌类型之一）中侵袭性和转移表型的关键调节剂。 SHARP 1受p63转移抑制剂的调节，并通过抑制缺氧诱导因子Ia（HIF-1α）和HIF-2a（HIFs）抑制TNBC侵袭性。 SHARP1反对体外依赖HIF的TNBC细胞迁移，以及体内的侵袭或转移行为。 SHARP 1是必需的，并且足以限制HIF靶基因的表达。在原发性TNBC中，内源性SHARP 1水平与HIF目标水平负相关。从机理上讲，SHARP 1与HIF结合，并通过充当蛋白酶体的HIF呈递因子来促进HIF蛋白酶体降解。此过程与pVHL（冯·希珀尔-林道肿瘤抑制因子），缺氧和遍在机制无关。因此，SHARP 1决定了HIF蛋白与氧水平平行并协同作用的内在不稳定性。这项工作揭示了TNBC获得侵袭性和转移倾向的机制和途径。

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  • 来源
    《Nature》 |2012年第7407期|p.380-384|共5页
  • 作者

    Marco Montagner; Elena Enzo; Mattia Forcato; Francesca Zanconato; Anna Parenti; Elena Rampazzo; Giuseppe Basso; Genesio Leo; Antonio Rosato; Silvio Bicciato; Michelangelo Cordenonsi; Stefano Piccolo;

  • 作者单位

    Department of Medical Biotechnologies, University of Padua School of Medicine, Viale Colombo 3,35131 Padua, Italy;

    Department of Medical Biotechnologies, University of Padua School of Medicine, Viale Colombo 3,35131 Padua, Italy;

    Center for Genome Research, Department of Biomedical Sciences, University of Modena and Reggio Emilia, Via G. Campi 287,41100 Modena, Italy;

    Department of Medical Biotechnologies, University of Padua School of Medicine, Viale Colombo 3,35131 Padua, Italy;

    Department of Medical Diagnostic Science and Special Therapies, Section of Pathology, University of Padua, Viale Gabelli 2,35126 Padua, Italy;

    Clinical and Experimental Hematology, Department of Pediatrics, University of Padova, Via Giustiniani 3,35128 Padova, Italy;

    Clinical and Experimental Hematology, Department of Pediatrics, University of Padova, Via Giustiniani 3,35128 Padova, Italy;

    Division of Anatomic Pathology, Hospital San Bassiano, Via dei Lotti 40,36061 Bassano del Grappa, Italy;

    Department of Surgery, Oncology and Gastroenterology, and Istituto Oncologico Veneto IRCCS, Via Gattamelata 64,35126 Padua, Italy;

    Center for Genome Research, Department of Biomedical Sciences, University of Modena and Reggio Emilia, Via G. Campi 287,41100 Modena, Italy;

    Department of Medical Biotechnologies, University of Padua School of Medicine, Viale Colombo 3,35131 Padua, Italy;

    Department of Medical Biotechnologies, University of Padua School of Medicine, Viale Colombo 3,35131 Padua, Italy;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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