Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
Molecular and Cellular Biology Program, Stony Brook University, Stony Brook, NY 11794, USA.
Carcinogenesis. 2023 Aug 18;44(6):485-496. doi: 10.1093/carcin/bgad048.
The chromobox-containing protein CBX4 is an important regulator of epithelial cell proliferation and differentiation, and has been implicated in several cancer types. The cancer stem cell (CSC) population is a key driver of metastasis and recurrence. The undifferentiated, plastic state characteristic of CSCs relies on cues from the microenvironment. Cancer-associated fibroblasts (CAFs) are a major component of the microenvironment that can influence the CSC population through the secretion of extracellular matrix and a variety of growth factors. Here we show CBX4 is a critical regulator of the CSC phenotype in squamous cell carcinomas of the skin and hypopharynx. Moreover, CAFs can promote the expression of CBX4 in the CSC population through the secretion of interleukin-6 (IL-6). IL-6 activates JAK/STAT3 signaling to increase ∆Np63α-a key transcription factor that is essential for epithelial stem cell function and the maintenance of proliferative potential that is capable of regulating CBX4. Targeting the JAK/STAT3 axis or CBX4 directly suppresses the aggressive phenotype of CSCs and represents a novel opportunity for therapeutic intervention.
染色盒蛋白 CBX4 是上皮细胞增殖和分化的重要调节因子，与几种癌症类型有关。癌症干细胞（CSC）群体是转移和复发的关键驱动因素。CSC 的未分化、可塑性特征依赖于微环境的信号。癌症相关成纤维细胞（CAF）是微环境的主要组成部分，通过分泌细胞外基质和各种生长因子影响 CSC 群体。在这里，我们表明 CBX4 是皮肤和下咽鳞状细胞癌中 CSC 表型的关键调节因子。此外，CAF 可以通过分泌白细胞介素 6（IL-6）促进 CSC 群体中 CBX4 的表达。IL-6 激活 JAK/STAT3 信号通路，增加 ∆Np63α-一种关键的转录因子，对于上皮干细胞功能和维持增殖潜能至关重要，能够调节 CBX4。靶向 JAK/STAT3 轴或 CBX4 直接抑制 CSC 的侵袭表型，为治疗干预提供了新的机会。
