ATAD2 drives melanoma growth and progression and inhibits ferroptosis
Year: 2025
Type: article
Abstract: Melanoma is a highly metastatic form of skin cancer for which current therapies offer limited benefits. We show here that the histone reader ATAD2 is overexpressed in melanoma and predicts poor prognosis, and that the MAP kinase pathway, via the transcription factor E2F1, stimulates ATAD2 expression. Genetic or pharmacological inhibition of ATAD2 suppresses the growth and metastasis of BRAF and NRAS mutant melanoma. Mechanistically, we show that ATAD2 inhibition activates both distinct and common tumor-suppressive pathways in BRAF and NRAS mutant melanoma. In particular, we find that ATAD2 inhibition induces ferroptosis in both contexts by downregulating the ferroptosis suppressor GPX4. The ferroptosis inducer erastin also inhibits melanoma growth. Combining the ATAD2 inhibitor BAY-850 with the MEK inhibitor trametinib potently suppresses melanoma growth. Our study identifies ATAD2 as a key driver of melanoma and provides a rationale for targeting ATAD2 in conjunction with the MAPK pathway to treat melanoma.
Source: EMBO Reports
Authors: Ashok Mari, Kevin Graciano, Raj Kumar, Emily Giles, Patrick T Ball, Revu V L Narayana, Romi Gupta
Language: English
Topic: Melanoma and MAPK Pathways
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $7,990
Awards: G1122925425, G4229164520, A Novel Anoikis Effector that Drives Ovarian Cancer Metastasis, G4798138178, G5838669946, PERSONALIZED THERAPY FOR p16-DEFICIENT MELANOMA, A NOVEL EPIGENETIC IMMUNOTHERAPY FOR OVARIAN CANCER TREATMENT, G7389101018, Comprehensive Cancer Center Support Grant, PRECISION METABOLIC THERAPY OF p53 MUTANT TRIPLE NEGATIVE BREAST CANCERS
OpenAlex ID: W4416915272