Figure 6: HIF-2α expression is required for SAHA’s efficacy in an autochthonous UPS model.

(a) Top: schematic of tracking autochthonous KP tumour growth in DMSO- and SAHA-treated mice. After Ad-Cre injection, mice were imaged bi-weekly until tumours were detectable and measured ∼50–100 mm³. Mice were randomized to DMSO control (n=5) or SAHA (n=5; 50 mg kg⁻¹ per day) treatments, and tumour growth was followed by bi-weekly CT scans. Bottom: representative axial CT images of KP mice pre- and post-treatment with DMSO or SAHA. Dashed white line demarcates the tumour boundary. (b) Relative sizes of individual tumours from KP mice receiving DMSO or SAHA treatment. (c) Comparison of the relative sizes of all DMSO- and SAHA-treated KP tumours at the time of killing (error bars are±s.e.m.). *P<0.05. P-values were calculated from a two-tailed Student’s t-test. (d) Weights of KP mice pre-treatment and at time of killing (error bars are±s.e.m.). Black squares, DMSO-treated mice; red circles, SAHA-treated mice. (e) Immunoblot of HIF-2α protein in KP autochthonous tumours from DMSO- and SAHA-treated mice. GAPDH served as loading control. (f) Left: representative transverse CT images of KPH2 mice pre- and post-treatment with DMSO or SAHA. Mice were treated and imaged as described in a. Right: relative sizes of individual tumours from KPH2 mice receiving DMSO (n=4) or SAHA (n=5) treatment. (g) Comparison of the relative sizes of all DMSO- and SAHA-treated KPH2 tumours at the time of killing (error bars are ±s.e.m.). (h) Model of EPAS1 regulation in the STS examined. EPAS1 expression is epigenetically downregulated through class I/II HDACs. Loss of HIF-2α increases ANO1 and calcium signalling, which subsequently increases mTORC1 activity in tumours and promotes sarcoma proliferation. HIF-2α loss may also increase sarcoma growth independent of this pathway.