Department and Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, 10051, Taiwan.
Department of Internal Medicine, National Taiwan University Hospital, Taipei, 100225, Taiwan.
Cancer Gene Ther. 2024 Nov;31(11):1734-1748. doi: 10.1038/s41417-024-00838-9. Epub 2024 Oct 2.
Colorectal cancer (CRC) is a common cancer worldwide with an increasing annual incidence. Cancer stem cells (CSCs) play important roles in the occurrence, development, recurrence, and metastasis of CRC. The molecular mechanism regulating the development of colorectal CSCs remains unclear. The discovery of human induced pluripotent stem cells (hiPSCs) through somatic cell reprogramming has revolutionized the fields of stem cell biology and translational medicine. In the present study, we converted hiPSCs into cancer stem-like cells by culture with conditioned medium (CM) from CRC cells. These transformed cells, termed hiPSC-CSCs, displayed cancer stem-like properties, including a spheroid morphology and the expression of both pluripotency and CSC markers. HiPSC-CSCs showed tumorigenic and metastatic abilities in mouse models. The epithelial-mesenchymal transition phenotype was observed in hiPSC-CSCs, which promoted their migration and angiogenesis. Interestingly, upregulation of C-MYC was observed during the differentiation of hiPSC-CSCs. Mechanistically, CREB binding protein (CBP) bound to the C-MYC promoter, while histone deacetylase 1 and 3 (HDAC1/3) dissociated from the promoter, ultimately leading to an increase in histone acetylation and C-MYC transcriptional activation during the differentiation of hiPSC-CSCs. Pharmacological treatment with a CBP inhibitor or abrogation of CBP expression with a CRISPR/Cas9-based strategy reduced the stemness of hiPSC-CSCs. This study demonstrates for the first time that colorectal CSCs can be generated from hiPSCs. The upregulation of C-MYC via histone acetylation plays a crucial role during the conversion process. Inhibition of CBP is a potential strategy for attenuating the stemness of colorectal CSCs.
结直肠癌（CRC）是一种常见的癌症，全球发病率呈上升趋势。癌症干细胞（CSC）在 CRC 的发生、发展、复发和转移中发挥重要作用。调节结直肠 CSC 发生的分子机制尚不清楚。通过体细胞重编程发现人类诱导多能干细胞（hiPSC）彻底改变了干细胞生物学和转化医学领域。在本研究中，我们通过 CRC 细胞的条件培养基（CM）培养将 hiPSC 转化为癌症干细胞样细胞。这些转化细胞被称为 hiPSC-CSCs，表现出癌症干细胞样特性，包括球体形态以及多能性和 CSC 标志物的表达。hiPSC-CSCs 在小鼠模型中具有致瘤和转移能力。在 hiPSC-CSCs 中观察到上皮-间充质转化表型，促进了它们的迁移和血管生成。有趣的是，在 hiPSC-CSCs 的分化过程中观察到 C-MYC 的上调。在机制上，CREB 结合蛋白（CBP）与 C-MYC 启动子结合，而组蛋白去乙酰化酶 1 和 3（HDAC1/3）与启动子解离，最终导致 hiPSC-CSCs 分化过程中组蛋白乙酰化增加和 C-MYC 转录激活。用 CBP 抑制剂进行药物治疗或使用基于 CRISPR/Cas9 的策略敲除 CBP 表达，可降低 hiPSC-CSCs 的干性。这项研究首次证明结直肠 CSCs 可以从 hiPSC 中产生。组蛋白乙酰化导致 C-MYC 的上调在转化过程中发挥关键作用。抑制 CBP 可能是降低结直肠 CSCs 干性的一种潜在策略。
