Targeting HBO1 Restores Paclitaxel Sensitivity via Suppression of ABCB1 and Hippo Pathway in Adriamycin-Resistant Breast Cancer

<title>Abstract</title> <p>Chemoresistance remains a major barrier to durable therapeutic responses in breast cancer. The histone acetyltransferase HBO1 (KAT7) has been linked to tumor progression, but its role in acquired chemoresistance is not well defined. Here, we investigated the contribution of HBO1 to drug resistance in adriamycin-resistant breast cancer cells (MCF7/ADR). HBO1 expression and H3K14 acetylation were markedly elevated in MCF7/ADR cells compared with parental MCF7 cells, concomitant with increased expression of the multidrug resistance transporter ABCB1. Moreover, Hippo pathway effectors YAP, TAZ, and pan-TEAD, as well as canonical Hippo target genes including ANKRD1, AXL, BIRC5, CDX2, CTGF, CYR61, and TEAD4, were robustly upregulated in resistant cells. Genetic silencing of HBO1 or pharmacological inhibition with the selective HBO1 inhibitor WM‑3835 reduced H3K14 acetylation and downregulated ABCB1 and key Hippo signaling components. Functionally, WM‑3835 potentiated the antitumor activity of paclitaxel in MCF7/ADR cells, leading to reduced viability, colony formation, migration, and spheroid growth, together with increased apoptotic cell death. In vivo, combined WM‑3835 and paclitaxel treatment achieved superior tumor growth suppression compared with either monotherapy in an MCF7/ADR xenograft model, without significant loss of body weight. Collectively, these findings identify HBO1 as a central epigenetic regulator of chemoresistance in breast cancer and demonstrate that HBO1 inhibition can restore chemosensitivity through coordinated suppression of ABCB1 expression and Hippo signaling. Our results nominate HBO1 targeting, in combination with paclitaxel, as a promising therapeutic strategy to overcome HBO1-mediated chemoresistance in breast cancer.</p>