American Association for Cancer Research
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Supplementary Data - Figures and Legends from Targeting Histone Chaperone FACT Complex Overcomes 5-Fluorouracil Resistance in Colon Cancer

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posted on 2023-04-03, 18:06 authored by Heyu Song, Jiping Zeng, Shrabasti Roychoudhury, Pranjal Biswas, Bhopal Mohapatra, Sutapa Ray, Kayvon Dowlatshahi, Jing Wang, Vimla Band, Geoffrey Talmon, Kishor K. Bhakat

Figure S1. IC50 decreased after APE1 knockdown. Figure S2. MMS increased colocalization of APE1 and FACT complex. Figure S3. FACT knockdown did not affect total APE1 level but decreased the occupancy of APE1 to p21 and DTL promoters. Figure S4. CBL0137 had minimal toxicity on cells. Figure S5. Combination of 5-FU and curaxins significantly inhibited xenograft growth. Figure S6. High expression of AcAPE1 and SSRP1 was observed in dMMR patients.

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NIH

NCI

Nebraska Department of Health and Human Services

Nebraska Research Initiative and Fred and Pamela Buffet Cancer Center

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ARTICLE ABSTRACT

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.

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