SOX30, a novel epigenetic silenced tumor suppressor, promotes tumor cell apoptosis by transcriptional activating p53 in lung cancer

Abstract

Although members of SOX family have been well documented for their essential roles in embryonic development, cell proliferation and disease, the functional role and molecular mechanism of SOX30 in cancer are largely unexplored. Here, we first identified SRY-box containing gene 30 (SOX30) as a novel preferentially methylated gene using genome-wide methylation screening. SOX30 hypermethylation was detected in 100% of lung cancer cell lines (9/9) and 70.83% (85/120) of primary lung tumor tissues compared with none (0/20) of normal and 8.0% (2/25) of peri-tumoral lung tissues (P<0.01). SOX30 was expressed in normal and peri-tumoral lung tissues in which SOX30 was unmethylated, but was silenced or downregulated in lung cancer cell lines and primary lung tumor tissues harboring a hypermethylated SOX30. De-methylation experiments further confirmed that silence of SOX30 was regulated by its hypermethylation. Ectopic expression of SOX30 induces cancer cell apoptosis with inhibiting proliferation in vitro and represses tumor formation in vivo, whereas knockdown of SOX30 demonstrates a reversed effect both in vitro and in vivo. At the molecular level, the antitumorigenic effect of SOX30 is mediated by directly binding to CACTTTG (+115 to +121) of p53 promoter region and activating p53 transcription, suggesting that SOX30 is a novel transcriptional activating factor of p53. Indeed, blockade of p53 attenuates the tumor inhibition of SOX30. Overall, these findings demonstrate that SOX30 is a novel epigenetic silenced tumor suppressor acting through direct regulation of p53 transcription and expression. This study provides novel insights on the mechanism of tumorigenesis in lung cancer.

Ski regulates Smads and TAZ signaling to suppress lung cancer progression

“…DNA methylation is a common mechanism of tumor suppressor gene inactivation and tumorigenesis . Recent studies have demonstrated that a series of methylation‐silenced tumor suppressor genes are associated with lung cancer progression …”

Role of the SOX18 protein in neoplastic processes (Review)

“…The representatives of the group F of SOX proteins are the proteins SOX7, SOX17 and SOX18, jointly involved in the development of the cardiovascular and lymphatic systems during the embryogenesis process (27,28). Since the main characteristic of these proteins is their high homology, they are able to take over each other's functions, as demonstrated in a mouse model where the inhibition of the SOX18 gene expression resulted in an increased expression of the SOX7 and SOX17 gene (29).…”

Toxicity and Pharmacokinetic Studies of Aerosolized Clinical Grade Azacitidine

“…On the other hand, in cancer, the majority of TSGs are silenced and their reactivation can have a beneficial impact on cell cycle repression and apoptosis and exert therapeutic effects 404142 . Because it has been demonstrated that hypermethylation of promoter regions of TSGs is one of the major epigenetic alterations in lung cancer development 434142 , treating the respiratory epithelium with demethylating agents would help tip the scales toward tumor suppression. Further detailed investigations however, should be pursued to uncover whether Aza can hypomethylate the promoter of oncogenes in cancers and its impact on potential cancer development.…”