RNA Polymerase I activity prevents terminal differentiation and growth arrest in colorectal cancer and induce vulnerability for senolytics

Loss of the tumor suppressor APC, which constitutes the initiating event in the adenoma carcinoma sequence for colorectal cancer (CRC), induces expression of RNA polymerase I (RNAPOL1) transcription machinery and subsequently upregulates rDNA transcription. Targeting RNAPOL1 with a specific inhibitor, CX5461, disrupts nucleolar integrity and induces a disbalance of ribosomal proteins. CX5461-induced growth arrest is irreversible, and exhibits features of senescence as well as terminal differentiation. Mechanistically, CX5461 promotes differentiation in a MIZ1- and Rb-dependent manner. In addition, inhibition of RNAPOL1 renders CRC cells vulnerable towards senolytic agents. RNA-seq of LS174T cells treated with CX5461