RAB4A is a master regulator of cancer cell stemness upstream of NUMB–NOTCH signaling

麻木的 SOX2 Notch信号通路 调节器 细胞生物学 生物 癌症干细胞 RAC1 基因敲除 癌症研究 癌细胞 干细胞 癌变 上皮-间质转换 癌症 信号转导 胚胎干细胞 转移 细胞培养 遗传学 基因
作者
Subbulakshmi Karthikeyan,Patrick J. Casey,Mei Wang
出处
期刊:Cell Death and Disease [Springer Nature]
卷期号:15 (10)
标识
DOI:10.1038/s41419-024-07172-w
摘要

Abstract Cancer stem cells (CSCs) are a group of specially programmed tumor cells that possess the characteristics of perpetual cell renewal, increased invasiveness, and often, drug resistance. Hence, eliminating CSCs is a major challenge for cancer treatment. Understanding the cellular programs that maintain CSCs, and identifying the critical regulators for such programs, are major undertakings in both basic and translational cancer research. Recently, we have reported that RAB4A is a major regulator of epithelial-to-mesenchymal transition (EMT) and it does so mainly through regulating the activation of RAC1 GTPase. In the current study, we have delineated a new signaling circuitry through which RAB4A transmits its control of cancer stemness. Using in vitro and in vivo studies, we show that RAB4A, as the upstream regulator, relays signal stepwise to NUMB, NOTCH1, RAC1, and then SOX2 to control the self-renewal property of multiple cancer cells of diverse tissue origins. Knockdown of NUMB, or overexpression of NICD (the active fragment NOTCH1) or SOX2, rescued the in vitro sphere-forming and in vivo tumor-forming abilities that were lost upon RAB4A knockdown. Furthermore, we discovered that the chain of control is mostly through transcriptional regulation at every step of the pathway. The discovery of the novel signaling axis of RAB4A–NUMB–NOTCH–SOX2 opens the path for further expansion of the signaling chain and for the identification of new regulators and interacting proteins important for CSC functions, which can be explored to develop new and effective therapies.
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