Suppression of FGFR3- and MYC-dependent oncogenesis by tubacin: association with HDAC6-dependent and independent activities

Abstract

Fibroblast growth factor receptor 3 (FGFR3) is amplified, translocated or mutated in a number of different human cancer types, but most commonly in bladder cancers. We previously found that the accumulation of FGFR3 is dependent on histone deacetylase 6 (HDAC6). Here we show that HDAC6 loss or inhibition reduces FGFR3 accumulation in cells made tumorigenic by ectopic expression of a mutant activated version of FGFR3 together with the MYC oncoprotein and in a bladder cancer cell line whose tumorigenicity is dependent on expression of a translocated version of FGFR3. In tumor xenoplant assays, HDAC6 deficiency or small molecule inhibition by the selective HDAC6 inhibitors tubacin or tubastatin A was found to significantly impede tumor growth. However, tubacin was more effective at inhibiting tumor growth than tubastatin A or HDAC6 deficiency. The superior anti-tumor activity of tubacin was linked to its ability to not only inhibit accumulation of mutant FGFR3, but also to cause robust downregulation of MYC and cyclin D1, and to induce a DNA damage response and apoptosis. Neither HDAC6 deficiency nor treatment with tubastatin A altered MYC or cyclin D1 levels, and neither induced a DNA damage response or apoptosis. Thus while tubacin and tubastatin A inhibit HDAC6 with similar selectivity and potency, our results reveal unique HDAC6-independent activities of tubacin that likely contribute to its potent anti-tumor activity.