Fig. 6: The PINK1-HNF4A axis drives the DNA damage-repair switch.
From: Early tolerance and late persistence as alternative drug responses in cancer
a Gene ontology analysis of up-regulated genes in HCT116 cells genetically silenced for PINK1 expression (n = 3 experimental replicates; mean ± SD). The most pertinent functions were ranked by -Log10(p-value). b Ingenuity pathway analysis for upstream regulators performed on differentially expressed genes in persisters and transcription factors ranked for their significance (-Log10 p-value). The Venn diagram represents overlap of HNF4A targets and deregulated genes upon PINK1 silencing. c. Proximity Ligation Assay (PLA) foci quantified as PLA puncta/nuclei in HT29 SCR and shPINK1 conditions (Scale bar: 10 μm). Significant differences among groups were quantified by applying two-sided Student’s t-test (n: SCR = 92; shPINK1 = 61; P = 0.0003). d Confocal acquisition of immunofluorescence staining in HT29 cells for PINK1 and HNF4A. Nuclei were counterstained with DAPI. Scale Bar: 7 µm. e Quantification of HNF4A nuclei fluorescence performed by using Cell Profiler 4.2.1. Significant differences among groups were calculated by applying ANOVA followed by Tukey post-test (***P = 0.0002; **P = 0.0062). f Western blot and protein level quantification in HT29 silenced for PINK1 and an SCR control. g MCRC PDO17 infected to silence PINK1 or a SCR control and then treated with FOLFOX or FOLFIRI for one week. The dotted line represents a drug holiday. Significant differences among conditions were calculated by two-sided Student’s t-test (n = 3 experimental repeats; mean ± SEM). h Kaplan-Meier curves representing Disease Free Survival (DFS) in CRC patients, divided at the median expression of a mitophagy signature. Significant differences among low and high-risk population were calculated by Log-Rank test (HR: Hazard Ratio). Source data are provided as a Source Data file.
