European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, Groningen 9713 AV, The Netherlands.
Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen 9713 AV, The Netherlands.
G3 (Bethesda). 2021 Dec 8;11(12). doi: 10.1093/g3journal/jkab335.
Maternal embryonic leucine zipper kinase (MELK) is frequently overexpressed in cancer, but the role of MELK in cancer is still poorly understood. MELK was shown to have roles in many cancer-associated processes including tumor growth, chemotherapy resistance, and tumor recurrence. To determine whether the frequent overexpression of MELK can be exploited in therapy, we performed a high-throughput screen using a library of Saccharomyces cerevisiae mutants to identify genes whose functions become essential when MELK is overexpressed. We identified two such genes: LAG2 and HDA3. LAG2 encodes an inhibitor of the Skp, Cullin, F-box containing (SCF) ubiquitin-ligase complex, while HDA3 encodes a subunit of the HDA1 histone deacetylase complex. We find that one of these synthetic lethal interactions is conserved in mammalian cells, as inhibition of a human homolog of HDA3 (Histone Deacetylase 4, HDAC4) is synthetically toxic in MELK overexpression cells. Altogether, our work identified a novel potential drug target for tumors that overexpress MELK.
母源胚胎亮氨酸拉链激酶（MELK）在癌症中经常过表达，但 MELK 在癌症中的作用仍知之甚少。MELK 在许多与癌症相关的过程中发挥作用，包括肿瘤生长、化疗耐药和肿瘤复发。为了确定 MELK 的频繁过表达是否可以在治疗中得到利用，我们使用酿酒酵母突变体文库进行了高通量筛选，以鉴定当 MELK 过表达时其功能变得必不可少的基因。我们鉴定出了两个这样的基因：LAG2 和 HDA3。LAG2 编码 Skp、Cullin、F-box 包含（SCF）泛素连接酶复合物的抑制剂，而 HDA3 编码 HDA1 组蛋白去乙酰化酶复合物的一个亚基。我们发现这些合成致死相互作用中的一个在哺乳动物细胞中是保守的，因为抑制人类同源物 HDA3（组蛋白去乙酰化酶 4，HDAC4）在 MELK 过表达细胞中是合成毒性的。总之，我们的工作鉴定了一种新型的潜在药物靶点，可用于治疗过表达 MELK 的肿瘤。
