Dexamethasone inhibits stemness maintenance and enhances chemosensitivity of hepatocellular carcinoma stem cells by inducing deSUMOylation of HIF‑1α and Oct4

Abstract

It has been controversial whether patients with hepatocellular carcinoma (HCC) should receive glucocorticoid therapy during chemotherapy. Recent studies have demonstrated that glucocorticoids increase the therapeutic sensitivity of tumors to some chemotherapeutic drugs, but the specific mechanism remains unclear. In the present study, dexamethasone (Dex) was used to treat HCC stem cells. The results demonstrated that Dex reduced stemness maintenance and self-renewal of HCC stem cells, promoted epithelial-to-mesenchymal transition, inhibited migration and angiogenesis and, more importantly, increased cell sensitivity to the herpes simplex virus thymidine kinase/ganciclovir drug system in vitro and in vivo. Further mechanistic analyses demonstrated that Dex inhibited small ubiquitin-like modifier (SUMO) modification of several proteins in HCC stem cells, including hypoxia-inducible factor (HIF)-1α, an important hypoxia tolerance protein, and octamer-binding transcription factor 4 (Oct4), a crucial stemness maintenance protein. Inducing deSUMOylation of HIF-1α and Oct4 reduced their accumulation in the nucleus, thereby inhibiting tumor angiogenesis and stemness maintenance. These findings provide a new perspective to the study of the mechanism underlying the anti-hepatocarcinogenesis effects of Dex. Due to the few side effects of glucocorticoids at low doses and their anti-inflammatory effects, the appropriate combination of glucocorticoids and chemotherapeutic drugs is expected to improve the survival of HCC patients and their prognosis.

Dexamethasone promotes breast cancer stem cells in obese and not lean mice

“…On the contrary, several studies have shown that dexamethasone decreases Sox2 and thereby inhibits cancer stem cells. 24 , 25 In addition, similar to our study, dexamethasone did not promote Ror1 expression in pancreatic cells 24 (Figure 2C ). Together these results indicate that GCs are a regulator of Sox2 expression, however, its activation or inhibition is dependent upon the cell type and/or microenvironment.…”

“…In our study, we found that dexamethasone promoted expression of the pluripotency transcription factor Sox2 in both normal diet and obese mice (Figure 2B), potentially indicating that a longer treatment time may promote stemness in lean mice. On the contrary, several studies have shown that dexamethasone decreases Sox2 and thereby inhibits cancer stem cells 24,25 . In addition, similar to our study, dexamethasone did not promote Ror1 expression in pancreatic cells 24 (Figure 2C).…”

Dexamethasone promotes breast cancer stem cells in obese and not lean mice

“…2B), potentially indicating that a longer treatment time may promote stemness in lean mice. On the contrary, several studies have shown that dexamethasone decreases Sox2 and thereby inhibits cancer stem cells [24,25]. In addition, similar to our study, dexamethasone did not promote Ror1 expression in pancreatic cells [24] (Fig.…”

SENP2 Reduces Hepatocellular Carcinoma Stemness and Improves Sorafenib Sensitivity Through Inactivating the AKT/GSK3β/CTNNB1 Pathway

“…In HCC, several factors have been identified that are highly relevant to stemness, including p53 mutation, β-catenin mutation, and telomerase reverse transcriptase promoter mutation ( 28 ). Recently, it is also proposed that SUMOylation plays a key role in HCC stemness ( 29 ), which highlights the possibility of SENP2 as a regulator for HCC stemness. Meanwhile, as mentioned earlier, our study disclosed that SENP2 was decreased in CSCs of HCC cells.…”