Fluorouracil (5-FU) remains a first-line chemotherapeutic agent for colorectal cancer. However, a subset of colorectal cancer patients who have defective mismatch-repair (dMMR) pathway show resistance to 5-FU. Here, we demonstrate that the efficacy of 5-FU in dMMR colorectal cancer cells is largely dependent on the DNA base excision repair (BER) pathway. Downregulation of APE1, a key enzyme in the BER pathway, decreases IC50 of 5-FU in dMMR colorectal cancer cells by 10-fold. Furthermore, we discover that the facilitates chromatin transcription (FACT) complex facilitates 5-FU repair in DNA via promoting the recruitment and acetylation of APE1 (AcAPE1) to damage sites in chromatin. Downregulation of FACT affects 5-FU damage repair in DNA and sensitizes dMMR colorectal cancer cells to 5-FU. Targeting the FACT complex with curaxins, a class of small molecules, significantly improves the 5-FU efficacy in dMMR colorectal cancer in vitro (∼50-fold decrease in IC50) and in vivo xenograft models. We show that primary tumor tissues of colorectal cancer patients have higher FACT and AcAPE1 levels compared with adjacent nontumor tissues. Additionally, there is a strong clinical correlation of FACT and AcAPE1 levels with colorectal cancer patients' response to chemotherapy. Together, our study demonstrates that targeting FACT with curaxins is a promising strategy to overcome 5-FU resistance in dMMR colorectal cancer patients.

中文翻译：

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靶向组蛋白伴侣FACT复合物可克服结肠癌中的5-氟尿嘧啶耐药性。

氟尿嘧啶（5-FU）仍然是结直肠癌的一线化疗药物。但是，一部分具有错配修复（dMMR）缺陷的结直肠癌患者表现出对5-FU的耐药性。在这里，我们证明了5-FU在dMMR大肠癌细胞中的功效在很大程度上取决于DNA碱基切除修复（BER）途径。下调APE1是BER途径中的关键酶，可使dMMR大肠癌细胞中5-FU的IC50降低10倍。此外，我们发现促进染色质转录（FACT）复杂通过促进APE1（AcAPE1）募集和乙酰化对染色质中损伤位点促进DNA中的5-FU修复。FACT的下调影响DNA中的5-FU损伤修复，并使dMMR大肠癌细胞对5-FU敏感。以姜黄素为目标的FACT复合物，一类小分子，在体外和体内异种移植模型中，可显着提高dMMR大肠癌的5-FU疗效（IC50降低约50倍）。我们显示，与邻近的非肿瘤组织相比，大肠癌患者的原发性肿瘤组织具有更高的FACT和AcAPE1水平。此外，FACT和AcAPE1水平与大肠癌患者对化学疗法的反应之间存在密切的临床相关性。总之，我们的研究表明，以姜黄素为靶向的FACT是克服dMMR大肠癌患者对5-FU耐药的一种有前途的策略。我们显示，与邻近的非肿瘤组织相比，大肠癌患者的原发性肿瘤组织具有更高的FACT和AcAPE1水平。此外，FACT和AcAPE1水平与大肠癌患者对化学疗法的反应之间存在密切的临床相关性。总之，我们的研究表明，以姜黄素为靶向的FACT是克服dMMR大肠癌患者对5-FU耐药的一种有前途的策略。我们显示，与邻近的非肿瘤组织相比，大肠癌患者的原发性肿瘤组织具有更高的FACT和AcAPE1水平。此外，FACT和AcAPE1水平与大肠癌患者对化学疗法的反应之间存在密切的临床相关性。总之，我们的研究表明，以姜黄素为靶向的FACT是克服dMMR大肠癌患者对5-FU耐药的一种有前途的策略。