m1A Regulated Genes Modulate PI3K/AKT/mTOR and ErbB Pathways in Gastrointestinal Cancer

Abstract

BACKGROUND: Gene expression can be posttranscriptionally regulated by a complex network of proteins. N1-methyladenosine (m1A) is a newly validated RNA modification. However, little is known about both its influence and biogenesis in tumor development. METHODS: This study analyzed TCGA data of patients with five kinds of gastrointestinal (GI) cancers. Using data from cBioPortal, molecular features of the nine known m1A-related enzymes in GI cancers were investigated. Using a variety of bioinformatics approach, the impact of m1A regulators on its downstream signaling pathway was studied. To further confirm this regulation, the effect of m1A writer ALKBH3 knockdown was studied using RNA-seq data from published database. RESULTS: Dysregulation and multiple types of genetic alteration of putative m1A-related enzymes in tumor samples were observed. The ErbB and mTOR pathways with ErbB2, mTOR, and AKT1S1 hub genes were identified as being regulated by m1A-related enzymes. The expression of both ErbB2 and AKT1S1 was decreased after m1A writer ALKBH3 knockdown. Furthermore, Gene Ontology analysis revealed that m1A downstream genes were associated with cell proliferation, and the results showed that m1A genes are reliably linked to mTOR. CONCLUSION: This study demonstrated for the first time the dysregulation of m1A regulators in GI cancer and its signaling pathways and will contribute to the understanding of RNA modification in cancer.

Gene signatures and prognostic values of m1A-related regulatory genes in hepatocellular carcinoma

“…Another research suggested that m1A plays a dynamic role in responses to various conditions of stress and other physiological events 17 . Mounting evidence also supports that m1A-related regulatory gene alterations are closely connected to multiple diseases including esophageal carcinoma, colorectal adenocarcinoma, and bladder urothelial carcinoma 22,23 . However, the role of m1A RNA methylation in the development and prognosis of HCC remains unclear.…”

“…Research has shown that high expression of hTrm6p/hTrm61p m1A transmethylase was correlated with m1A levels in urine and the occurrence of bladder cancer 22 . Another study demonstrated that m1A-related regulatory genes were dysregulated in gastrointestinal cancer and associated with mTOR and ErbB pathways 23 . In addition, the alteration of DNA methylation was described in HCC and may act vital roles in tumorigenesis 24,25 .…”

Novel insight into the regulatory roles of diverse RNA modifications: Re-defining the bridge between transcription and translation

“…Hence, accumulated ALKBH3 means improved CSF-1 mRNA expression and invasion of cancer cells [141]. Subsequently, ALKBH3, considered the eraser of m 1 A, tightly correlates with the mTOR pathway in gastrointestinal cancer and is attributed to the limited expression of ErbB2 and AKT1S1 after ALKBH3 knockdown; the downstream genes of m 1 A are associated with cell proliferation according to Gene Ontology analysis [142]. Additionally, silencing of ALKBH3 arrests the cell cycle at the G1 phase and contributes to the progression, angiogenesis and invasion of urothelial carcinomas by modulating NADPH oxidase-2reactive oxygen species (NOX-2-ROX) and TNF-like weak inducer of apoptosis (TWEAK)/Fibroblast growth factor-inducible 14 (Fn14)-VEGF signals [143].…”

Epigenetic modulations of noncoding RNA: a novel dimension of Cancer biology

“…Nine members of m1A regulators have been identified till now including writers (TRMT6, TRMT61A, TRMT10C), readers (YTHDF1, YTHDC1) and erasers (ALKBH1, ALKBH3) [5,92,93]. Dysregulation of m1A components was found to promote the progression of gastric cancer and bladder cancer via activation of several oncogenic pathways such as PI3K/AKT/mTOR and ErbB Pathways [94]. However, whether m1A of ncRNAs were involved in these pathways remained obscure.…”