Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, California 91010, USA.
Department of Medical Oncology, City of Hope National Medical Center, Duarte, California 91010, USA.
Nat Commun. 2016 Jul 28;7:12326. doi: 10.1038/ncomms12326.
Cancer stem cells (CSCs) have key roles in treatment resistance, tumour metastasis and relapse. Using colorectal cancer (CC) cell lines, patient-derived xenograft (PDX) tissues and patient tissues, here we report that CC CSCs, which resist chemoradiation, have higher SUMO activating enzyme (E1) and global SUMOylation levels than non-CSCs. Knockdown of SUMO E1 or SUMO conjugating enzyme (E2) inhibits CC CSC maintenance and self-renewal, while overexpression of SUMO E1 or E2 increases CC cell stemness. We found that SUMOylation regulates CSCs through Oct-1, a transcription factor for aldehyde dehydrogenases (ALDHs). ALDH activity is not only a marker for CSCs but also important in CSC biology. SUMO does not modify Oct-1 directly, but regulates the expression of TRIM21 that enhances Oct-1 ubiquitination and, consequently, reducing Oct-1 stability. In summary, our findings suggest that SUMOylation could be a target to inhibit CSCs and ultimately to reduce treatment resistance, tumour metastasis and relapse.
癌症干细胞 (CSC) 在治疗抵抗、肿瘤转移和复发中起着关键作用。使用结直肠癌细胞系、患者来源的异种移植物 (PDX) 组织和患者组织，我们在此报告，抵抗放化疗的结直肠癌 CSC 具有更高的 SUMO 激活酶 (E1) 和全局 SUMO 化水平，而非 CSC。SUMO E1 或 SUMO 缀合酶 (E2) 的敲低抑制结直肠 CSC 的维持和自我更新，而 SUMO E1 或 E2 的过表达增加了结直肠细胞的干性。我们发现 SUMO 化通过醛脱氢酶 (ALDH) 的转录因子 Oct-1 来调节 CSC。ALDH 活性不仅是 CSC 的标志物，而且在 CSC 生物学中也很重要。SUMO 不能直接修饰 Oct-1，而是调节 TRIM21 的表达，增强 Oct-1 的泛素化，从而降低 Oct-1 的稳定性。总之，我们的研究结果表明，SUMO 化可能是抑制 CSC 的靶点，并最终降低治疗抵抗、肿瘤转移和复发的风险。
