Proximity of pre-mRNA 3′ end processing and transcription termination is associated with enhanced gene expression

Two key factors required for pre-mRNA 3' end processing, CPSF73 and PCF11, are linked to poor cancer prognosis, yet their oncogenic roles remain unclear due to their dual function in transcription termination. Using a colorectal cancer (CRC) progression model, we show that primary tumor cells depend on high CPSF73 and PCF11 levels, whereas metastatic cells are less sensitive. This dependency is not explained by alternative polyadenylation (APA) or transcription-replication conflicts. Instead, we identify an uncoupling of 3' cleavage and transcription termination during CRC progression. Primary tumor cells exhibit a global shift toward proximal termination alongside distal APA usage, while metastatic cells partially revert to normal termination patterns and favor proximal APA. Notably, the distance between 3' cleavage and termination is nearly halved in primary tumor cells compared with normal cells and becomes particularly short in oncogenes. Reduced cleavage-termination distance correlates with increased gene expression both within and across cell states. These findings identify a previously unrecognized link between transcription termination architecture and gene expression regulation.