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

IF 8.1 1区 生物学 Q1 CELL BIOLOGY
Subbulakshmi Karthikeyan, Patrick J Casey, Mei Wang
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引用次数: 0

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.

RAB4A 是 NUMB-NOTCH 信号转导上游的癌细胞干性主调节因子。
癌症干细胞(CSCs)是一组经过特殊编程的肿瘤细胞,具有细胞永续更新、侵袭性增强以及耐药性等特点。因此,消除癌症干细胞是癌症治疗的一大挑战。了解维持 CSCs 的细胞程序并确定这些程序的关键调控因子是癌症基础研究和转化研究的主要任务。最近,我们报道了 RAB4A 是上皮细胞向间质转化(EMT)的主要调控因子,它主要通过调控 RAC1 GTPase 的活化来实现这一目的。在目前的研究中,我们勾勒出了一个新的信号回路,RAB4A通过该回路传递其对癌症干性的控制。通过体外和体内研究,我们发现 RAB4A 作为上游调控因子,将信号逐步传递给 NUMB、NOTCH1、RAC1,然后再传递给 SOX2,以控制不同组织来源的多种癌细胞的自我更新特性。敲除 NUMB 或过量表达 NICD(NOTCH1 的活性片段)或 SOX2 可挽救因敲除 RAB4A 而丧失的体外形成球和体内形成肿瘤的能力。此外,我们还发现,在该通路的每一步中,控制链主要是通过转录调控实现的。RAB4A-NUMB-NOTCH-SOX2这一新型信号轴的发现为进一步扩展信号链、鉴定对CSC功能有重要作用的新调节因子和相互作用蛋白开辟了道路,这些调节因子和相互作用蛋白可用于开发新的有效疗法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cell Death & Disease
Cell Death & Disease CELL BIOLOGY-
CiteScore
15.10
自引率
2.20%
发文量
935
审稿时长
2 months
期刊介绍: Brought to readers by the editorial team of Cell Death & Differentiation, Cell Death & Disease is an online peer-reviewed journal specializing in translational cell death research. It covers a wide range of topics in experimental and internal medicine, including cancer, immunity, neuroscience, and now cancer metabolism. Cell Death & Disease seeks to encompass the breadth of translational implications of cell death, and topics of particular concentration will include, but are not limited to, the following: Experimental medicine Cancer Immunity Internal medicine Neuroscience Cancer metabolism
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