Newly identified C/EBPγ protein links cancer cell plasticity and DNA repair

A research team has uncovered a novel protein, C/EBPγ, that plays a dual role in cancer progression. This protein enhances both epithelial-mesenchymal transition (EMT) and DNA repair in lung adenocarcinoma cells, contributing to increased treatment resistance. EMT is a process where cancer cells acquire traits enabling them to move and invade surrounding tissues, often associated with tumor progression and therapy resistance.

Traditionally, EMT was thought to be regulated by distinct transcription factors, but C/EBPγ emerges as a unique regulator that connects EMT with DNA repair mechanisms. The discovery was made through an epigenomic analysis focusing on histone H3 lysine 4 trimethylation (H3K4me3), a chromatin signature linked to cell identity. By examining genes with expanded H3K4me3 domains during TGF-β-induced EMT, the researchers identified C/EBPγ as a key player.

Further experiments confirmed that introducing C/EBPγ into lung adenocarcinoma cells promoted hallmark EMT features, such as mesenchymal-like morphology and enhanced migratory capacity. Depleting endogenous C/EBPγ, however, suppressed these EMT-associated changes. The study also revealed that C/EBPγ operates through an unconventional mechanism, relying on its leucine zipper domain rather than its DNA-binding domain for biological activity.

This suggests that interactions with other proteins are crucial for its function. Proteomic analyses identified C/EBPβ and the DNA repair factors XRCC5 and XRCC6 as interacting partners of C/EBPγ. These interactions allow C/EBPγ to physically associate with XRCC5 and XRCC6, key components of the non-homologous end joining (NHEJ) pathway, which is essential for repairing DNA double-strand breaks.

C/EBPγ enhances NHEJ activity, leading to increased DNA repair efficiency and greater resistance to chemotherapy. In mouse models, tumors expressing C/EBPγ remained more resistant to etoposide treatment compared to control tumors, while disruption of C/EBPγ's leucine zipper domain abolished this protective effect. The findings suggest that C/EBPγ acts as a molecular hub, linking EMT-associated cellular reprogramming with enhanced DNA repair capacity.

By coordinating these two mechanisms, C/EBPγ may help cancer cells adapt to therapeutic stress and acquire treatment resistance. The researchers propose that targeting C/EBPγ or its protein-interaction interfaces could represent a new therapeutic strategy to improve the effectiveness of DNA-damaging therapies and overcome treatment resistance in lung adenocarcinoma.