ATAD2 drives melanoma growth and progression and inhibits ferroptosis

TL;DR

ATAD2 promotes melanoma growth and blocking it causes cancer cell death, suggesting it could be a new target for treatment.

Contribution

ATAD2 is identified as a melanoma driver whose inhibition induces ferroptosis and synergizes with MEK inhibitors.

Findings

ATAD2 overexpression is linked to poor prognosis in melanoma and is regulated by the MAPK–E2F1 pathway.

Inhibiting ATAD2 suppresses melanoma growth and metastasis by inducing ferroptosis through GPX4 downregulation.

Combining ATAD2 and MEK inhibitors enhances antitumor effects in melanoma.

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.

ATAD2 drives melanoma progression, and its inhibition induces ferroptosis to suppress tumor growth, supporting its potential as a therapeutic target for more effective melanoma treatment.

ATAD2 is overexpressed in melanoma, driven by the MAPK–E2F1 pathway, and is linked to poor prognosis.Inhibiting ATAD2 suppresses tumor growth and metastasis in melanoma by inducing ferroptosis via downregulation of GPX4.Combining ATAD2 inhibitor BAY-850 with MEK inhibitor trametinib enhances antitumor effects, supporting a dual-targeted therapeutic strategy.

ATAD2 is overexpressed in melanoma, driven by the MAPK–E2F1 pathway, and is linked to poor prognosis.

Inhibiting ATAD2 suppresses tumor growth and metastasis in melanoma by inducing ferroptosis via downregulation of GPX4.

Combining ATAD2 inhibitor BAY-850 with MEK inhibitor trametinib enhances antitumor effects, supporting a dual-targeted therapeutic strategy.

ATAD2 drives melanoma progression, and its inhibition induces ferroptosis to suppress tumor growth, supporting its potential as a therapeutic target for more effective melanoma treatment.

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