Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6, Canada; Goodman Cancer Research Centre, McGill University, 1160 Pine Avenue W, Montreal, QC H3A 1A3, Canada.
Goodman Cancer Research Centre, McGill University, 1160 Pine Avenue W, Montreal, QC H3A 1A3, Canada.
Mol Cell. 2019 Jul 25;75(2):340-356.e10. doi: 10.1016/j.molcel.2019.05.033. Epub 2019 Jun 26.
The microRNAs encoded by the miR-17∼92 polycistron are commonly overexpressed in cancer and orchestrate a wide range of oncogenic functions. Here, we identify a mechanism for miR-17∼92 oncogenic function through the disruption of endogenous microRNA (miRNA) processing. We show that, upon oncogenic overexpression of the miR-17∼92 primary transcript (pri-miR-17∼92), the microprocessor complex remains associated with partially processed intermediates that aberrantly accumulate. These intermediates reflect a series of hierarchical and conserved steps in the early processing of the pri-miR-17∼92 transcript. Encumbrance of the microprocessor by miR-17∼92 intermediates leads to the broad but selective downregulation of co-expressed polycistronic miRNAs, including miRNAs derived from tumor-suppressive miR-34b/c and from the Dlk1-Dio3 polycistrons. We propose that the identified steps of polycistronic miR-17∼92 biogenesis contribute to the oncogenic re-wiring of gene regulation networks. Our results reveal previously unappreciated functional paradigms for polycistronic miRNAs in cancer.
miR-17∼92 多顺反子编码的 microRNAs 在癌症中通常过表达，并协调广泛的致癌功能。在这里，我们通过破坏内源性 microRNA（miRNA）加工来确定 miR-17∼92 致癌功能的机制。我们表明，在 miR-17∼92 初级转录物（pri-miR-17∼92）的致癌过表达时，微处理器复合物仍然与异常积累的部分加工中间体结合。这些中间体反映了 pri-miR-17∼92 转录本早期加工中的一系列层次和保守步骤。miR-17∼92 中间体对微处理器的阻碍导致共表达的多顺反子 miRNAs 的广泛但选择性下调，包括来自肿瘤抑制 miR-34b/c 和来自 Dlk1-Dio3 多顺反子的 miRNAs。我们提出，鉴定的多顺反子 miR-17∼92 生物发生步骤有助于基因调控网络的致癌重布线。我们的研究结果揭示了多顺反子 miRNAs 在癌症中的以前未被认识到的功能范例。
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