Tanshinone Suppresses Arecoline-Induced EpithelialMesenchymal Transition in Oral Submucous Fibrosis by Epigenetically Reactivating the p53 Pathway

Abstract

Oral submucous fibrosis (OSF) induced by chewing of the areca nut has been considered to be a precancerous lesion with a high probability of developing oral squamous cell carcinoma. Tanshinone (TSN) is the main component extracted from , a traditional Chinese medicine, which was found to have diverse pharmacological effects, such as anti-inflammatory and antitumor. In the current study, we aimed to identify the inhibitory effects and the underlying mechanism of TSN on OSF progress. We found that treatment with TSN inhibited the arecoline-mediated proliferation of primary human oral mucosal fibroblasts and reversed the promotive effects of arecoline on the EMT process. By RNA deep sequencing, we screened two possible targets for TSN: LSD1 and p53. We confirmed that p53 is much lower in OSF than in normal mucous tissues. In addition, p53 and its downstream molecules were decreased by arecoline treatment in oral mucosal fibroblasts, which was reversed by treatment with TSN in a dose-dependent manner. Our results also revealed that arecoline stimulation resulted in hypermethylation of the promoter of and subsequent downregulation of p53 levels, which was reversed by TSN. Furthermore, we identified that LSD1 could epigenetically activate by recruiting H3K27me1 and H3K4m2 to its promoter. Our findings provide new insights into the mechanism by which TSN influences arecoline-induced OSF and rationale for the development of clinical intervention strategies for OSF and even oral squamous cell carcinoma.

Oral Submucous Fibrosis: A Review on Etiopathogenesis, Diagnosis, and Therapy

“…This material consists of dihydrotanshinone I, tanshinone I, and tanshinone IIA and has anti-inflammatory and antioxidant activity. Tanshinone epigenetically interacts with the p53 pathway which is downregulated in OSF [135]. Salvianolic acid B is also extracted from Salvia miltiorrhiza.…”

“…Decrease α-SMA and fibronectin and type 1 collagen A1 expression Inhibit myofibroblast activity (migration and contraction) [75] Glabridin Decrease α-SMA, type I collagen, and TGF-β Inhibit myofibroblast activity (migration and contraction) [131] Asiatic acid Inhibit TGF-β1, collagen 1 type 2, and collagen 3 type 1 [134] Tanshinone reactivate p53 [135] Salvianolic acid B with Triamcinolone acetonide…”

Tanshinones in management of oral submucous fibrosis and oral squamous cell carcinoma

“…Arecoline treatment of oral mucosal fibroblasts resulted in reduction of p53 and its related downstream molecules p21, Bax, and p53 upregulated modulator of apoptosis (PUMA). [7] Arecoline promoted hypermethylation of promoter of p53, which was reversed by TSN. In G1-S phase cell cycle, the repair of damaged DNA is facilitated by p53 protein.…”

“…[10] The authors suggested that TSN could be of help in intervention against OSMF and OSCC. [7] Ding et al investigated the radiosensitizing effects of TIIA on human OSCC. The authors observed that TIIA significantly sensitized SCC090 OSCC cells to radiation through enhanced reactive oxygen species generation and autophagy.…”

“…TSN decreased the expression of proliferative marker Ki67 in tumor sections of SCC-9 xenografts. [7] TSNs inhibit invasion and metastasis of cancer cells by altering matrix metalloproteinases. [9] TSN is synergistic with anticancer drugs, such as cisplatin, 5-fluorouracil, doxorubicin, and arsenic trioxide.…”