Mutations in tumour suppressor p53 confer enhanced metastasis and chemoresistance in colorectal cancer (CRC). Though the genetic events regulating CRC with p53 loss/mutation have been documented, the epigenetic events accompanying the loss of p53 have not been well understood. Epigenome based classification of CRC tumours has identified the active enhancer mark as a distinct marker for progression, however the role of the distal regulatory regions upon p53 loss in CRC remains to be established. This work investigates the influence of p53 loss on enhancer regulation in colorectal cancer cells. Genome wide profiling of active enhancer mark, H3K27ac in p53wt and p53-/- CRC cells reveal an overall gain of this mark around the promoters and intronic regions. These active enhancers show strong association with oncogenes and hallmark MYC and E2F targets suggesting an enhancer mediated regulation of MYC/E2F pathway governed by E2Fs, MAZ and PATZ1. Interestingly, we also observed a gain in oncogenic super enhancers mediated by E2Fs/KLFs accompanying loss of p53. The promoters of histone methyl transferases EZH2 and SuV39H1 (E2F targets) show elevated levels of H3K27ac suggesting a novel epigenetic regulation of CRC around the promoters and distal regulatory regions. Our validation of these findings in p53 deficient colon cancer cohorts shows that the super enhancer associated genes align more to the CMS4 subtype and exhibit lower survivability. The observed cancer stemness and gain of oncogenic super enhancers with p53 loss presents a hitherto unexplored paradigm of enhancer mediated oncogenic progression which may be exploited for devising epigenetic therapy in p53-/- CRC patients.
Rani et al. (Sat,) studied this question.