Hypoxia-inducible factor-1 alpha (HIF-1α) 是明確定義的促癌轉錄因子，其功能為活化下游基因的表現量來促進癌症進程。DiGeorge syndrome chromosomal region 8 (DGCR8) 是一個可以參與在微小核糖核酸生合成的多功能性核醣核酸結合蛋白，最近被意外的發現可以結合其他種類的核醣核酸。微小核糖核酸表現量已經被發現在人類惡性腫瘤中呈現全面性的降低，部分可能的解釋為其切割因子Dicer以及Drosha的表現量降低。然而，上升的DGCR8表現量在多種人類惡性腫瘤中被觀察到，卻沒有陳述其相關分子機制。核糖核酸監視系統是由演化保留度高的溶解性核糖核酸exosome複合體主導，執行核糖核酸切割以及品質管理。具功能的exosome複合體是由中心蛋白以及核糖核酸溶解性酵素組成，例如RRP6 (EXO10RRP6)。在這個研究中，我們意外地觀察到HIF-1α與DGCR8結合以促成DGCR8/RRP6複合體的組裝，並且接著抑制微小核仁核糖核酸的表現量。微小核仁核糖核酸U50是一個可以抑制KRAS所主導的腫瘤發生過程的腫瘤抑制因子，並且被發現為HIF-1α/DGCR8/Exo10RRP6複合體的重要標靶。藉由增強此核糖核酸exosome複合體，HIF-1α抑制U50表現並且促進乳癌細胞的致癌特性。我們將以DGCR8為中心的微小核糖核酸切割複合體分子轉換機制稱為‘Exoswitch’，此為HIF-1α在調控微小非編碼核糖核酸平衡中，獨立於其轉錄活性的一個重要功能。綜觀來說，我們的結果解釋了DGCR8在癌症中表現量上升的分子功能，此為需要HIF-1α促進的Exoswitch來降解腫瘤抑制性的微小核仁核糖核酸U50，最後導致增強的乳癌細胞致癌特性。

Hypoxia-inducible factor-1 alpha (HIF-1α) has been well-defined as an oncogenic transcription factor which activates the expression of downstream genes to promote cancer progression. DiGeorge syndrome chromosomal region 8 (DGCR8), is a multifunctional RNA binding protein that participates in miRNA biogenesis and was recently discovered to unexpectedly recognize other RNA species. Global reduction of miRNAs in human malignancies have been observed, which could be partially explained by the downregulation their processing factors Dicer and Drosha. However, elevated DGCR8 level was observed in multiple types of human malignancies without demonstration of its molecular basis. RNA surveillance system is mediated by evolutionary conserved ribonucleolytic RNA exosome complex which mediates RNA processing and quality control. A functional exosome complex is composed of core proteins and ribonucleolytic enzyme, such as RRP6 (EXO10RRP6). In this study, we unexpectedly observed that HIF-1α protein interacts with DGCR8 to facilitate DGCR8/RRP6 complex assembly and subsequently downregulates snoRNA expression. The snoRNA U50, a putative tumor suppressor inhibiting KRAS-mediated tumorigenesis, was identified as a novel target for HIF-1α/DGCR8/Exo10RRP6. Through enhancing this exosome complex, HIF-1α downregulated U50 and promoted oncogenic properties of breast cancer. We termed the DGCR8-centered molecular shift between two small RNA-processing complexes as ‘Exoswitch’ which is a novel function of HIF-1α in regulating small non-coding RNA homeostasis independently of its transcriptional activity. Taken together, our results explained the molecular function of DGCR8 overexpression in cancer, which required HIF-1α-triggered Exoswitch to degrade tumor suppressive snoRNA U50, and eventually led to enhanced tumorigenic properties of breast cancer.

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