FTO mediated ERBB2 demethylation promotes tumor progression in esophageal squamous cell carcinoma cells

Abstract

N6-methyladenosine (m6A) is the most prevalent and internal modification that occurs in the messenger RNAs of eukaryotes. However, knowledge of the impact of these modifications on gene expression regulation remains limited. By using the in vitro MeRIP-seq and RNA-seq assays, we discovered that the mRNA demethylase FTO was significantly up-regulated in esophageal squamous cell carcinoma (ESCC) tissues and cells. Knockdown of FTO drastically suppressed the proliferation, migration, and invasion of ESCC cells. Furthermore, by using transcriptome-wide m6A-seq and RNA-seq assays, we identified ERBB2 is the target of FTO, which acts in concert in ESCC tumorigenesis and metastasis. Moreover, loss and gain functional studies suggested that the m6A reader YTHDF1 stabilizes ERBB2 mRNA via decoding the m6A modification. All these results uncovered a new signaling cascade, including FTO, YTHDF1, and ERBB2, which finely regulates the ESCC progression.

The Role of m6A Modification and m6A Regulators in Esophageal Cancer

“…It is generally acknowledged that YTHDF1 plays a facilitating role in translation initiation and protein synthesis [ 10 ]. That was true in the study from Zhao et al [ 73 ], which demonstrated that YTHDF1 upregulated the protein level of ERBB2 through recognizing m 6 A-modified ERBB2 mRNA. Conversely, the knockdown of YTHDF1 enhanced the protein level of HSD17B11, which suggested that YTHDF1 decreased the translation efficiency of m 6 A-modified HSD17B11 mRNA [ 74 ].…”

“…Thus, the A allele of rs5746136 in SOD2 was associated with a reduced risk of bladder cancer [ 57 ]. m 6 A could deposit on various type of RNA, such as coding RNA and non-coding RNA, participate in all steps of RNA metabolism and post-transcriptionally regulate the expression of the gene ( Table 1 ) [ 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 ].…”

“…Most studies revealed that the m 6 A level was elevated in ESCC tissues and cell lines [ 73 , 84 , 85 , 86 ]. However, Cui et al [ 83 ] found lower m 6 A levels in ESCC cell lines and tissues compared to their counterparts.…”

“…The expression, clinical significance and biological function of m 6 A regulators in ESCA are shown in Supplementary Table S1 [ 59 , 60 , 61 , 66 , 69 , 72 , 73 , 74 , 75 , 76 , 79 , 80 , 83 , 84 , 85 , 86 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 ].…”

ERBB2 promoter demethylation and immune cell infiltration promote a poor prognosis for cancer patients

“…In the TCGA cases, we observed a significant negative correlation between ERBB2 DNA methylation and gene mutation at the promoter region. Integrating gene expression and DNA methylation data obtained from gene mutation analysis were compared with DNA methylation analysis to identify genes that were significantly altered in DNA methylation ( 22 ).…”