Joint Centers for Systems Biology, Columbia University, New York, NY, USA.
Oncogene. 2013 Nov 7;32(45):5283-91. doi: 10.1038/onc.2012.543. Epub 2012 Nov 26.
The MYC protooncogene is associated with the pathogenesis of most human neoplasia. Conversely, its experimental inactivation elicits oncogene addiction. Besides constituting a formidable therapeutic target, MYC also has an essential function in normal physiology, thus creating the need for context-specific targeting strategies. The analysis of post-translational MYC activity modulation yields novel targets for MYC inactivation. Specifically, following regulatory network analysis in human B-cells, we identify a novel role of the STK38 kinase as a regulator of MYC activity and a candidate target for abrogating tumorigenesis in MYC-addicted lymphoma. We found that STK38 regulates MYC protein stability and turnover in a kinase activity-dependent manner. STK38 kinase inactivation abrogates apoptosis following B-cell receptor activation, whereas its silencing significantly decreases MYC levels and increases apoptosis. Moreover, STK38 knockdown suppresses growth of MYC-addicted tumors in vivo, thus providing a novel viable target for treating these malignancies.
原癌基因 MYC 与大多数人类肿瘤的发病机制有关。相反，其实验性失活会引发致癌基因成瘾。除了构成一个强大的治疗靶点外，MYC 在正常生理中也具有重要功能，因此需要有针对性的靶向策略。对 MYC 翻译后活性调节的分析产生了 MYC 失活的新靶标。具体来说，在对人类 B 细胞的调控网络分析后，我们确定了 STK38 激酶作为 MYC 活性调节剂的新作用，以及作为消除 MYC 成瘾性淋巴瘤肿瘤发生的候选靶标。我们发现 STK38 以激酶活性依赖的方式调节 MYC 蛋白的稳定性和周转率。STK38 激酶失活可阻止 B 细胞受体激活后的细胞凋亡，而其沉默则显著降低 MYC 水平并增加细胞凋亡。此外，STK38 敲低可抑制体内 MYC 成瘾性肿瘤的生长，因此为治疗这些恶性肿瘤提供了一个新的可行靶点。
