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E2F4-p53 Re-ChIP seq in HCT116 p21-/- cells & HCT116 p53-/- TAD mutant cells

ABSTRACT: E2F4-p53 Re-ChIP seq in HCT116 p21-/- cells & HCT116 p53-/- TAD mutant cells

PROVIDER: PRJEB82783 | ENA |

REPOSITORIES: ENA

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Project description:Colorectal cancer (CRC) continues to be the third most common cancer globally, often diagnosed at advanced stages due to a lack of early biomarkers. Current therapeutic methods frequently exhibit variable efficacy, highlighting the need for new treatment strategies. Metformin, a widely used antihyperglycemic agent, has recently garnered attention for its potential anti-tumor properties. In this study, we evaluated the effects of tumor suppressor genes TP53 and CDKN1A (p21) on the efficacy of metformin in a KRAS-mutant CRC model, HCT116 cells (harboring a G13D mutation in KRAS). Using the parental (p53+/+, p21+/+) cells and isogenic knockout (KO) versions for p53 and p21, we assessed cell viability, cell cycle distribution, and their transcriptomic responses to metformin treatment. Metformin significantly reduced cell proliferation in a dose- and time-dependent manner, with parental cells exhibiting the greatest sensitivity (approximately 20% viability reduction at 2 mM and 40% reduction at 10 mM after 24 h, p<0.05; and a 40% viability reduction at 5 mM and 60-70% reduction at 10 mM after 48 h, p<0.01). The loss of p53 or p21 notably decreased this sensitivity, with p53 KO cells responding only after 48 h of treatment, and p21 KO cells responding only at the higher dose of 10 mM after an incubation time of 72 h. The cell cycle analysis indicated a substantial G0/G1 arrest in parental cells (from approximately 55% of untreated cells to around 65% with 8 mM metformin at 24 h, p<0.05), while p53-/- and p21-/- cells did not show significant arrest (p>0.05). Our transcriptomic profiling revealed extensive differential gene expression in parental cells (1399 DEGs; 902 downregulated, 497 upregulated), in contrast to the limited responses in p53-/- (270 DEGs) and p21-/- cells (32 DEGs). Importantly, key genes involved in DNA replication stress (FAM111A), MAPK signaling (DUSP5), and inflammation modulation (TNFAIP3) were commonly regulated across the genotypes. Our findings emphasize that metformin’s antiproliferative effects in KRAS-mutant CRC are significantly influenced by the p53–p21 tumor suppressor axis, offering a more defined rationale for genotype-based precision oncology strategies.

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E2F4-p53 Re-ChIP seq in HCT116 p21-/- cells & HCT116 p53-/- TAD mutant cells

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