Gal-1 promotes lung cancer cell survival by enhancing PARP1/H1.2 interaction to promote DNA repair upon DNA damage response.

Abstract

Galectin-1 (Gal-1), a member of the galectin family, has emerged as a regulator of tumor progression. Several studies have reported the upregulation of Gal-1 expression in multiple cancer cells and its promotion on tumor proliferation. However, the mechanism by which Gal-1 promotes tumor growth remains to be thoroughly understood. In this study, it was discovered that high expression of Gal-1 in various cancers was inversely correlated with the overall survival of patients. Through constructing Gal-1-overexpressing cell lines, it was uncovered that cell proliferation and colony formation were significantly improved. The results of transcriptomic and proximity-labeling-based proteomic analyses indicated that Gal-1 interacted with poly [ADP-ribose] polymerase 1 (PARP1) and histone H1.2 in lung cancer cells. In the case of etoposide treatment leading to DNA double-strand break, Gal-1 accelerated the degradation of H1.2 by enhancing its interaction with PARP1 and promoting its PARylation. It caused the activation of downstream DNA repair pathways such as the serine-protein kinase ATM and nibrin (NBS1) signaling pathways, thus reducing apoptosis, and the Gal-1 inhibitor thiodigalactoside (TDG) could restore cell sensitivity to etoposide. Upon knockdown of Gal-1, DNA damage led to impaired activation of ATM and NBS1 phosphorylation, thereby increasing the sensitivity of the A549 cell line to etoposide. Finally, using a tumor-bearing mouse model, we observed that, in tumors with high Gal-1 expression, the combination treatment of TDG and etoposide significantly inhibited tumor growth. This study provides new clues for the role of Gal-1 in the development of tumors and renders suggestions for the medication of patients with high Gal-1 expression in the clinic.