c-MYC empowers transcription and productive splicing of the oncogenic splicing factor Sam68 in cancer
c-MYC empowers transcription and productive splicing of the oncogenic splicing factor Sam68 in cancer
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DOI：
10.1093/nar/gkz344
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发表时间：
2019-07-09
影响因子：
14.9
通讯作者：
Bielli, Pamela
中科院分区：
文献类型：
--
作者：
Caggiano, Cinzia;Pieraccioli, Marco;Bielli, Pamela
剪接因子Sam 68在许多人类癌症中上调，包括前列腺癌（PCa），其中它促进细胞增殖和存活。然而，尽管其在癌症中频繁上调，但其表达的潜在机制在很大程度上是未知的。在此，生物信息学分析鉴定了Sam 68基因的启动子区域（KHDRBS 1）和原癌基因转录因子c-MYC作为Sam 68表达的关键调节因子。在PCa患者中，Sam 68和c-MYC的上调相关。c-MYC直接结合并激活Sam 68启动子。此外，c-MYC通过调节基因内的转录延伸率来影响新生Sam 68转录物的生产性剪接。重要的是，Sam 68的c-MYC依赖性表达受到外部信号（如雄激素和/或有丝分裂原）的严格控制。这些发现揭示了c-MYC对Sam 68的转录和剪接的意想不到的协调，这可能代表了PCa肿瘤发生的关键步骤。
The splicing factor Sam68 is upregulated in many human cancers, including prostate cancer (PCa) where it promotes cell proliferation and survival. Nevertheless, in spite of its frequent upregulation in cancer, the mechanism(s) underlying its expression are largely unknown. Herein, bioinformatics analyses identified the promoter region of the Sam68 gene (KHDRBS1) and the proto-oncogenic transcription factor c-MYC as a key regulator of Sam68 expression. Upregulation of Sam68 and c-MYC correlate in PCa patients. c-MYC directly binds to and activates the Sam68 promoter. Furthermore, c-MYC affects productive splicing of the nascent Sam68 transcript by modulating the transcriptional elongation rate within the gene. Importantly, c-MYC-dependent expression of Sam68 is under the tight control of external cues, such as androgens and/or mitogens. These findings uncover an unexpected coordination of transcription and splicing of Sam68 by c-MYC, which may represent a key step in PCa tumorigenesis.