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oai:figshare.com:article/32641758 2026-10-01T16:20:47Z portal_1172 item_type_8 month_year_10_2026

Investigation of novel avenues for cancer treatment and mechanisms of post-stress recovery Xiyuan Qi (24170226) PUREID: 656342256 Ribosome biogenesis RNA polymerase I inhibitors KDM4A 5-Fluorouracil Colorectal cancer This thesis investigates novel therapeutic approaches for colorectal cancer (CRC) and explores the molecular mechanisms underlying cellular stress responses, focusing on RNA Polymerase I inhibitors (PIis) and the histone demethylase KDM4A. The research demonstrates that PIis (PMR-116, CX-5461, and BMH-21) exhibit potent anti-tumour effects against CRC cells regardless of p53 status, with BMH-21 showing the highest efficacy. Transcriptomic analysis revealed early gene expression changes primarily affecting chromatin organisation pathways. Importantly, combining low concentrations of PIis with 5-fluorouracil (5-FU) produced synergistic anti-cancer effects in p53-proficient cells, characterised by enhanced G2/M arrest and increased apoptosis. This synergy appears to result from the convergence of nucleolar stress response (NSR) and DNA damage response pathways, leading to amplified p53 activation and downstream signalling, probably combined with a stimulation of the p53-independent NSR pathway. Comprehensive multi-omics analysis identified KDM4A as a master coordinator of stress-mediated transcriptional changes. Integration of ChIP-seq, RNA-seq, and functional validation studies revealed that KDM4A orchestrates comprehensive cellular adaptation to stress through four distinct regulatory mechanisms targeting specific gene programs. KDM4A coordinates both immediate stress adaptation and preparation for recovery by simultaneously activating stress response programs while suppressing energy-intensive processes. Notably, depletion of KDM4A significantly enhanced the sensitivity of CRC cells to PIis and 5-FU in a p53-dependent manner, with pronounced cytotoxic effects observed in wild-type but not p53-null cells. Immunofluorescence analysis demonstrated that PIis disrupt the spatial relationship between KDM4A and RNA Polymerase I within the nucleolus, suggesting a mechanistic basis for this enhanced sensitivity. Together, these findings establish PIis as promising therapeutic agents for CRC, particularly in combination with 5-FU, and identify KDM4A as a key coordinator of stress response and drug sensitivity. This research advances our understanding of epigenetic regulation during stress and suggests new approaches for cancer treatment that exploit the convergence of nucleolar stress and DNA damage response pathways, potentially addressing challenges of chemotherapy resistance in colorectal cancer. 2026-10-01T16:20:47Z Text Thesis 10.17034/32641758.v1 https://figshare.com/articles/thesis/Investigation_of_novel_avenues_for_cancer_treatment_and_mechanisms_of_post-stress_recovery/32641758 All Rights Reserved