SHARP1 suppresses breast cancer metastasis by promoting degradation of hypoxia-inducible factors
SHARP1 suppresses breast cancer metastasis by promoting degradation of hypoxia-inducible factors
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DOI：
10.1038/nature11207
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发表时间：
2012-07-19
期刊：
影响因子：
64.8
通讯作者：
Piccolo, Stefano
中科院分区：
文献类型：
--
作者：
Montagner, Marco;Enzo, Elena;Piccolo, Stefano
乳腺癌中恶性细胞行为的分子决定因素仅部分了解（1）。在这里，我们表明SHARP 1（也称为BHLHE 41或DEC 2）是三阴性乳腺癌（TNBC）中侵袭性和转移性表型的关键调节因子，TNBC是最具侵袭性的乳腺癌类型之一。SHARP 1受p63转移抑制因子调节，并通过抑制缺氧诱导因子1 α（HIF-1 α）和HIF-2 α（HIF）抑制TNBC侵袭性。SHARP 1在体外对抗HIF依赖性TNBC细胞迁移，在体内对抗侵袭或转移行为。SHARP 1是限制HIF靶基因表达所必需的，也是足够的。在原发性TNBC中，内源性SHARP 1水平与HIF靶点的水平呈负相关。SHARP 1与HIF结合，作为HIF蛋白酶体的递呈因子，促进HIF蛋白酶体的降解。该过程不依赖于pVHL（von Hippel-Lindau肿瘤抑制因子）、缺氧和泛素化机制。因此，SHARP 1决定了HIF蛋白质的内在不稳定性，以与氧水平平行并与其合作。这项工作揭示了TNBC获得侵袭性和转移倾向的机制和途径。
The molecular determinants of malignant cell behaviours in breast cancer remain only partially understood(1). 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. SHARP1 is regulated by the p63 metastasis suppressor and inhibits TNBC aggressiveness through inhibition of hypoxia-inducible factor 1 alpha (HIF-1 alpha) and HIF-2 alpha (HIFs). SHARP1 opposes HIF-dependent TNBC cell migration in vitro, and invasive or metastatic behaviours in vivo. SHARP1 is required, and sufficient, to limit expression of HIF-target genes. In primary TNBC, endogenous SHARP1 levels are inversely correlated with those of HIF targets. Mechanistically, SHARP1 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 ubiquitination machinery. SHARP1 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.