Targeting Histone Chaperone FACT Complex Overcomes 5-Fluorouracil Resistance in Colon Cancer

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 IC 50 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 IC 50 ) 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.

APE1 interacts with the nuclear exosome complex protein MTR4 and is involved in cisplatin‐ and 5‐fluorouracil‐induced RNA damage response

“…The chemoresistance of the therapeutic agent 5‐FU, used for the treatment of CRC, is also linked to BER. In particular, a lower activity of BER in tumour tissue can be considered a good prognostic factor [64] while increased acetylation of APE1 negatively correlates with the effectiveness of 5‐FU treatment in colorectal cancer (CRC) patients [65]. Moreover, APE1‐deficiency sensitizes CRC cells defective for MMR to 5‐FU [65].…”

The Prognostic Significance of Global Histones Deacetylation in Colorectal Cancer Patients Treated with Fluoropyrimdine Therapy

“…As known, CRC patients with de icient mismatch repair are highly associated with high-frequency microsatellite and better clinical outcome (Battaglin et al, 2018). However, their response to 5-FU exhibited resistance which was dependent on the DNA base excision repair pathway in Roos and Krumm (2016) and on Wnt pathway and checkpoint kinase 1 (CHK1) pathway in He et al (2018) Chromatin Transcription (FACT) complex facilitates 5-FU repair in DNA via promoting the recruitment and acetylation of APE1 (AcAPE1) to the damage sites in chromatin (Song et al, 2020). Besides Chung et al (2010) demonstrated the role of mismatch repair gene (hMLH1) dependency on 5FU induced H3 hypoacetylation for DNA access promoting the resistance to cell death during the G 1 /S phase of the cell cycle.…”

Histone Chaperones and Digestive Cancer: A Review of the Literature

“…Five studies have found SSRP1 to be overexpressed in digestive cancer, but only one study has reported SPT16 to be overexpressed [ 12 , 22 , 25 , 26 , 28 ]. In Gut , an elegant experimental and clinical study by Shen [ 12 ] elucidates the close and targetable relationships existing between the KEAP1/NRF2 pathway and the FACT complex in HCC cells.…”