Fig. 6: Activation of MC1R signaling dampens HCC growth.
From: TET2 orchestrates YAP signaling to potentiate targetable vulnerability in hepatocellular carcinoma
A Vitamin C promotes the expression of MC1R and phosphorylation level of YAP Ser127 via activation of TET2 in HCC cells. Cells were treated with 1 mM vitamin C for 24 h. B Vitamin C can enhance the suppressive effect of α-MSH on YAP activity in HCC cells. Cells were treated with 1 mM vitamin C for 24 h and 2 μM α-MSH for 1 h. C, D Vitamin C can enhance the anticancer effect of α-MSH in HCC cells. Cells were treated with 2 μM α-MSH alone or combination of 1 mM vitamin C and 2 μM α-MSH for different times as indicated (left panel). α-MSH concentration was measured (right panel). E Vitamin C and α-MSH can overcome sorafenib resistance in sorafenib-resistant MHCC97H cells. Cells were treated with 2 μM α-MSH alone or combination of 1 mM vitamin C and 2 μM α-MSH for three days. Vitamin C enhances the anticancer effect of α-MSH in vivo. Tumor image (F), tumor volume (G) and tumor weight (H) were monitored with four weeks after transplantation. n = 6 independent animals. I TET2 stimulates transcription of MC1R via oxidation of 5mC involved in its promoter, which can be enhanced by vitamin C. Afterwards, MC1R boosts cAMP-PKA signaling in both ligand dependent and independent manner to repress YAP activity. Combination of vitamin C and α-MSH can distinctly dampen tumor growth. Data are presented as mean ± s.d., n = 3 independent repeats. Unpaired, two-tailed t-test.
