FOXJ1 regulates microtubule dynamics in nonciliated cells and is a mediator of taxane resistance

Docetaxel is the first-line chemotherapy for metastatic castration-resistant prostate cancer (PC) and taxanes are broadly used in other cancers, but mechanisms of resistance remain to be established. In our study, we generated docetaxel-resistant PC xenografts and found increased expression of genes that drive development of multiciliated cells. These genes included FOXJ1, its upstream activator GMNC, and multiple FOXJ1-regulated genes that are associated with microtubules (MTs). Notably, FOXJ1 gene amplification was more frequent in taxane-exposed PC patients, and its overexpression conferred resistance to docetaxel both in vitro and in vivo. This resistance was associated with a decrease in docetaxel-mediated MT bundling, indicating that FOXJ1-regulated genes act at the level of tubulin to mitigate abnormal MT aggregation. Additionally, overexpression of an MT-associated FOXJ1-regulated gene (TPPP3) had similar effects. Conversely, FOXJ1 knockdown impaired basal MT function, enhanced taxane binding to MTs, and increased docetaxel sensitivity. Finally, analysis of data from the CHAARTED clinical trial showed that higher expression of FOXJ1 was predictive of decreased survival in PC patients treated with docetaxel. Together these findings highlight FOXJ1's role in regulating MT dynamics in non-ciliated cells and that its increased expression mediates taxane resistance. Overall design: Mice with LuCaP35CR or LuCaP70CR xenograft tumors were treated with either vehicle or docetaxel (DTX) at 30 mg/kg by i.p. injection every 21 days starting at day 0 as indicated. Docetaxel and vehicle treated xenografts were harvested when they reached ~1500 mm3. The treated tumors were harvested 2 weeks after their final dose of docetaxel. Mice bearing LNCaP FOXJ1_OE and LNCaP EV xenografts were treated with docetaxel (DTX, 30 mg/kg, i.p., 6 mice per each group). The first dose was administered when tumors reached ~250 mm3 (Day 9), and a second dose was given on Day 30. Mice for both groups were sacrificed 5 days after the second dose, and the tumors were harvested for RNA sequencing.