Molecular Pathology Unit, Center for Cancer Research, and Center for Systems Biology, Massachusetts General Hospital, 149 13 Street, Charlestown, MA 02129.
Mol Cancer Res. 2013 Sep;11(9):1072-7. doi: 10.1158/1541-7786.MCR-13-0040-T. Epub 2013 May 30.
Activating point mutations in K-RAS are extremely common in cancers of the lung, colon, and pancreas and are highly predictive of poor therapeutic response. One potential strategy for overcoming the deleterious effects of mutant K-RAS is to alter its posttranslational modification. Although therapies targeting farnesylation have been explored, and have ultimately failed, the therapeutic potential of targeting other modifications remains to be seen. Recently, it was shown that acetylation of lysine 104 attenuates K-RAS transforming activity by interfering with GEF-induced nucleotide exchange. Here, the deacetylases HDAC6 and SIRT2 were shown to regulate the acetylation state of K-RAS in cancer cells. By extension, inhibition of either of these enzymes has a dramatic impact on the growth properties of cancer cells expressing activation mutants of K-RAS. These results suggest that therapeutic targeting of HDAC6 and/or SIRT2 may represent a new way to treat cancers expressing mutant forms of K-RAS.
This study suggests that altering K-RAS acetylation is a feasible approach to limiting tumorigenic potential.
激活点突变 K-RAS 是在肺癌、结肠癌和胰腺癌中非常常见，并且高度预测不良的治疗反应。克服突变 K-RAS 的有害影响的一种潜在策略是改变其翻译后修饰。尽管已经探索了针对法呢基化的治疗方法，但最终都失败了，针对其他修饰的治疗潜力仍有待观察。最近，研究表明赖氨酸 104 的乙酰化通过干扰 GEF 诱导的核苷酸交换来减弱 K-RAS 的转化活性。在这里，去乙酰化酶 HDAC6 和 SIRT2 被显示在癌细胞中调节 K-RAS 的乙酰化状态。由此，抑制这些酶中的任何一种都会对表达 K-RAS 激活突变的癌细胞的生长特性产生巨大影响。这些结果表明，靶向 HDAC6 和/或 SIRT2 的治疗可能代表治疗表达突变形式的 K-RAS 的癌症的新方法。
本研究表明改变 K-RAS 乙酰化是限制肿瘤发生潜力的可行方法。
