Decreased Expression of Programmed Death Ligand-L1 by Seven in Absentia Homolog 2 in Cholangiocarcinoma Enhances T-Cell–Mediated Antitumor Activity

Abstract

N6-methyladenosine (m6A) has been reported as an important mechanism of post-transcriptional regulation. Programmed death ligand 1 (PD-L1) is a primary immune inhibitory molecule expressed on tumor cells that promotes immune evasion. In addition, seven in absentia homolog 2 (Siah2), a RING E3 ubiquitin ligase, has been involved in tumorigenesis and cancer progression. However, the role of m6A-METTL14-Siah2-PD-L1 axis in immunotherapy remains to be elucidated. In this study, we showed that METTL14, a component of the m6A methyltransferase complex, induced Siah2 expression in cholangiocarcinoma (CCA). METTL14 was shown to enrich m6A modifications in the 3’UTR region of the Siah2 mRNA, thereby promoting its degradation in an YTHDF2-dependent manner. Furthermore, co-immunoprecipitation experiments demonstrated that Siah2 interacted with PD-L1 by promoting its K63-linked ubiquitination. We also observed that in vitro and in vivo Siah2 knockdown inhibited T cells expansion and cytotoxicity by sustaining tumor cell PD-L1 expression. The METTL14-Siah2-PD-L1–regulating axis was further confirmed in human CCA specimens. Analysis of specimens from patients receiving anti-PD1 immunotherapy suggested that tumors with low Siah2 levels were more sensitive to anti-PD1 immunotherapy. Taken together, our results evidenced a new regulatory mechanism of Siah2 by METTL14-induced mRNA epigenetic modification and the potential role of Siah2 in cancer immunotherapy.

Role of m6A modification in female infertility and reproductive system diseases

“…Siah2 knockdown inhibited T cells expansion and cytotoxicity by sustaining tumor cell PD-L1 expression. Analysis of specimens from patients receiving anti-PD1 immunotherapy suggested that tumors with low Siah2 levels were more sensitive to anti-PD1 immunotherapy [70]. Whether this is effective in CC still remains to be studied.…”

Profiling of a novel circadian clock-related prognostic signature and its role in immune function and response to molecular targeted therapy in pancreatic cancer

“…FBXL17, FBXL8, CDK1, CSNK1D, and PSPC1 have not been well studied in pancreatic ductal cancer. However, several of them have been implicated in pancreatic cancer, with a relatively high expression and a poor survival [30][31][32][33]. These suggest that the 13 genes in this prognostic signature are worth further investigation for their potential as novel therapeutic targets.…”

Emerging roles of m6A RNA modification in cancer therapeutic resistance

“…METTL14 could enrich m6A in the 3'UTR of the siah E3 ubiquitin protein ligase 2 (SIAH2) mRNA and lead to YTHDF1-mediated decay. Therefore, deficiency of SIAH2 elevated PD-L1 expression level by reducing its K63-linked ubiquitination, and further sensitized tumor to ICB [ 136 ].…”