N⁶‐methyladenosine‐modified FAM111A‐DT promotes hepatocellular carcinoma growth via epigenetically activating FAM111A

Abstract

As an epitranscriptomic modulation manner, N6‐methyladenosine (m6A) modification plays important roles in various diseases, including hepatocellular carcinoma (HCC). m6A modification affects the fate of RNAs. The potential contributions of m6A to the functions of RNA still need further investigation. In this study, we identified long noncoding RNA FAM111A‐DT as an m6A‐modified RNA and confirmed three m6A sites on FAM111A‐DT. The m6A modification level of FAM111A‐DT was increased in HCC tissues and cell lines, and increased m6A level was correlated with poor survival of HCC patients. m6A modification increased the stability of FAM111A‐DT transcript, whose expression level showed similar clinical relevance to that of the m6A level of FAM111A‐DT. Functional assays found that only m6A‐modified FAM111A‐DT promoted HCC cellular proliferation, DNA replication, and HCC tumor growth. Mutation of m6A sites on FAM111A‐DT abolished the roles of FAM111A‐DT. Mechanistic investigations found that m6A‐modified FAM111A‐DT bound to FAM111A promoter and also interacted with m6A reader YTHDC1, which further bound and recruited histone demethylase KDM3B to FAM111A promoter, leading to the reduction of the repressive histone mark H3K9me2 and transcriptional activation of FAM111A. The expression of FAM111A was positively correlated with the m6A level of FAM111A‐DT, and the expression of methyltransferase complex, YTHDC1, and KDM3B in HCC tissues. Depletion of FAM111A largely attenuated the roles of m6A‐modified FAM111A‐DT in HCC. In summary, the m6A‐modified FAM111A‐DT/YTHDC1/KDM3B/FAM111A regulatory axis promoted HCC growth and represented a candidate therapeutic target for HCC.

Unravelling the Intricate Roles of FAM111A and FAM111B: From Protease-Mediated Cellular Processes to Disease Implications

“…Therefore, future studies are required to validate these hypotheses. Recently, long noncoding RNA (lncRNA) of FAM111A (known as FAM111A-divergent transcript or FAM111A-DT) have been shown to promote the progression and poor survival rate of hepatocellular carcinoma (HCC) through its modification by N 6 -methyladenosine (m 6 A) [ 37 ]. The m6A-modified FAM111DT was shown to drive the overexpression of wild-type FAM111A by activating the FAM111A promoter through interaction with the m6A-binding protein YTHDC1 and the recruitment of the histone demethylase KDM3B to FAM111A promoter.…”

“…The m6A-modified FAM111DT was shown to drive the overexpression of wild-type FAM111A by activating the FAM111A promoter through interaction with the m6A-binding protein YTHDC1 and the recruitment of the histone demethylase KDM3B to FAM111A promoter. Furthermore, this study showed that m6A-modified FAM111A-DT promoted HCC cellular proliferation, DNA replication and tumor growth, and mutation of m6A sites on FAM111A-DT abolished these roles [ 37 ] and could represent a viable treatment target for HCC. Additionally, other studies have associated FAM111A variants with prostate cancer predisposition [ 38 ], a novel prognostic and immunologic biomarker for diffuse lower-grade glioma [ 39 ] and early diagnostic indicator of gastric cancer [ 40 ], thus highlighting its essential role in the diagnosis and treatment of cancers.…”

RNA modifications in the progression of liver diseases: from fatty liver to cancer

“…YTHDF2 upregulates LncAY in HCC, and through promoting BMI1 expression, lncAY activates Wnt/β-catenin signaling (Chen et al, 2021b). Increased m 6 A modifications on the lncRNA FAM111A-DT further HCC progression by promoting FAM111A transcription through interactions with YTHDC1 (Pu et al, 2023). ALKBH5 is generally downregulated in HCC, and decreased demethylation of LINC01468 increased its expression, driving NAFLD-HCC progression through CUL4Alinked degradation of SHIP2 and subsequent activation of the PI3K/AKT/mTOR signaling pathway (Wang et al, 2022b).…”

Epigenetic roles of KDM3B and KDM3C in tumorigenesis and their therapeutic implications

“…KDM3B is recruited by N 6 -methyladenosine (m 6 A) reader, YTHDC1, to m 6 A-associated chromatin regions. Recruited KDM3B contributes to HCC progression by removing H3K9me2 on the promoter of FAM111A [ 34 , 35 ]. FAM111A, a single-stranded DNA-binding serine protease that promotes DNA synthesis, is reported to be increased in HCC and correlates with poor survival of HCC patients.…”