Nemo-like kinase (NLK) primes colorectal cancer progression by releasing the E2F1 complex from HDAC1.

Control of E2F1 activity is restricted via its interactions with RB1 and HDAC1. However, the detailed regulatory mechanisms underlying the E2F1/HDAC1 complex remain elusive. Here, we report that Nemo-like kinase (NLK) boosts cell cycle progression, which facilitates tumor development by releasing the E2F1 protein from HDAC1. Deletion of NLK largely blocks colorectal tumor proliferation and development. Moreover, RNA-seq shows that cell cycle is arrested at the G1/S phase in NLK-deficient cells and that the expression of E2F complex-targeted genes are affected, whereas overexpression of NLK but not an NLK mutant restores the wild-type phenotype. Mechanistically, we show that NLK interacts with the E2F1 complex, leading to disassembly of the E2F1/HDAC1 complex and thus diminishing the ability of E2F1 to bind to target gene promoters. Our results indicate that NLK boosts cell proliferation and E2F1 activity and controls the cell cycle switch by releasing HDAC1 from the E2F1 complex.