Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, K1H 8M5, Canada.
School of Pharmaceutical Sciences, Faculty of Medicine, University of Ottawa, Ottawa, ON, K1H 8M5, Canada.
Cancer Metastasis Rev. 2024 Mar;43(1):441-456. doi: 10.1007/s10555-023-10145-8. Epub 2023 Oct 4.
Sam68 (Src associated in mitosis of 68 kDa) is an RNA-binding and multifunctional protein extensively characterized in numerous cellular functions, such as RNA processing, cell cycle regulation, kinase- and growth factor signaling. Recent investigations highlighted Sam68 as a primary target of a class of reverse-turn peptidomimetic drugs, initially developed as inhibitors of Wnt/β-catenin mediated transcription. Further investigations on such compounds revealed their capacity to selectively eliminate cancer stem cell (CSC) activity upon engaging Sam68. This work highlighted previously unappreciated roles for Sam68 in the maintenance of neoplastic self-renewal and tumor-initiating functions. Here, we discuss the implication of Sam68 in tumorigenesis, where central findings support its contribution to chromatin regulation processes essential to CSCs. We also review advances in CSC-targeting drug discovery aiming to modulate Sam68 cellular distribution and protein-protein interactions. Ultimately, Sam68 constitutes a vulnerability point of CSCs and an attractive therapeutic target to impede neoplastic stemness in human tumors.
Sam68（与有丝分裂中 68 kDa 相关的Src）是一种 RNA 结合蛋白和多功能蛋白，在许多细胞功能中得到了广泛研究，如 RNA 处理、细胞周期调控、激酶和生长因子信号转导。最近的研究强调了 Sam68 是一类反向转角肽模拟药物的主要靶点，这些药物最初被开发为抑制 Wnt/β-catenin 介导的转录。对这些化合物的进一步研究表明，它们能够在与 Sam68 结合时选择性地消除癌症干细胞（CSC）的活性。这项工作突出了 Sam68 在维持肿瘤自我更新和肿瘤起始功能方面以前未被重视的作用。在这里，我们讨论了 Sam68 在肿瘤发生中的作用，其中核心发现支持它对染色质调节过程的贡献，这些过程对 CSCs 至关重要。我们还回顾了靶向 CSC 的药物发现的进展，旨在调节 Sam68 的细胞分布和蛋白-蛋白相互作用。最终，Sam68 构成了 CSCs 的脆弱点，是一种有吸引力的治疗靶点，可以阻止人类肿瘤中的肿瘤干性。
