PHRF1 (PHD and RING finger domain-containing protein 1) suppresses acute promyelocytic leukemia (APL) by promoting TGIF (TG-interacting factor) ubiquitination, while the PML-RARα protein interferes with PHRF1-mediated TGIF breakdown to facilitate APL. Beyond its role in APL tumorigenesis, PHRF1 contributes to non-homologous end-joining by linking H3K36 methylation and Nbs1 upon DNA damage insults. However, little is known regarding its function in tumor invasion. Here we highlight the unreported details of PHRF1 in the invasion of lung cancer cells by modulating the transcriptional level of ZEB1, a prominent regulator involved in epithelial-mesenchymal transition. PHRF1 associated with the phosphorylated C-terminal repeat domain of Rpb1, the large subunit of RNA polymerase II, through its C-terminal Set2 Rpb1 Interacting (SRI) domain. Chromatin immunoprecipitation revealed that PHRF1 bound to the proximal region adjacent to the transcription start site of ZEB1. SRI-deleted PHRF1 neither associated with Rpb1 nor increased ZEB1's expression. Collectively, PHRF1 might take the stage at migration and invasion by modulating the expression of ZEB1.