KIAA1429 promotes gastric cancer progression by destabilizing RASD1 mRNA in an m ⁶ A-YTHDF2-dependent manner.

Publisher: BioMed Central Country of Publication: England NLM ID: 101190741 Publication Model: Electronic Cited Medium: Internet ISSN: 1479-5876 (Electronic) Linking ISSN: 14795876 NLM ISO Abbreviation: J Transl Med Subsets: MEDLINE

Original Publication: [London] : BioMed Central, 2003-

Stomach Neoplasms*/genetics ; Stomach Neoplasms*/pathology ; Stomach Neoplasms*/metabolism ; RNA, Messenger*/metabolism ; RNA, Messenger*/genetics ; Disease Progression* ; Gene Expression Regulation, Neoplastic* ; RNA-Binding Proteins*/metabolism ; RNA-Binding Proteins*/genetics ; Cell Proliferation*/genetics ; RNA Stability*/genetics ; Adenosine*/analogs & derivatives ; Adenosine*/metabolism; Humans ; Cell Line, Tumor ; Animals ; Male ; Mice, Nude ; Female ; Middle Aged ; Cell Movement/genetics ; Mice ; Prognosis ; Mice, Inbred BALB C

Background: KIAA1429, a regulatory subunit of the N ⁶ -methyladenosine (m ⁶ A) methyltransferase complex, has been implicated in the progression of various cancers. However, the role of KIAA1429 in gastric cancer (GC) and its underlying mechanisms remain elusive. This study aimed to investigate the role of KIAA1429 in GC and to elucidate the underlying mechanisms.
Methods: The expression patterns and clinical relevance of KIAA1429 in GC were assessed using quantitative real-time PCR (qRT-PCR), Western blotting, immunohistochemistry (IHC), and bioinformatic analysis. In vitro and in vivo loss- and gain-of-function assays, m ⁶ A dot blot assays, methylated RNA immunoprecipitation sequencing (MeRIP-seq), RNA-seq, MeRIP-qPCR, dual luciferase reporter assays, RNA stability assays, RNA immunoprecipitation (RIP) assays, and RNA pull-down assays were performed to investigate the biological functions and underlying molecular mechanisms of KIAA1429 in GC.
Results: Both the mRNA and protein expression of KIAA1429 were greater in GC tissues than in normal gastric tissues. High KIAA1429 expression correlated positively with poor prognosis in GC patients. KIAA1429 not only promoted GC cell proliferation, colony formation, G2/M cell cycle transition, migration, and invasion in vitro but also enhanced GC tumor growth and metastasis in vivo. Mechanistically, KIAA1429 increased the m ⁶ A level of RASD1 mRNA and enhanced its stability in an m ⁶ A-YTHDF2-dependent manner, thereby upregulating its expression. RASD1 knockdown partially rescued the KIAA1429 knockdown-induced impairment of pro‑oncogenic ability in GC cells. The expression levels of KIAA1429 and RASD1 were negatively correlated in GC tissues.
Conclusions: KIAA1429 plays a pro‑oncogenic role in GC by downregulating RASD1 expression through destabilizing RASD1 mRNA in an m ⁶ A-YTHDF2-dependent manner. KIAA1429 may serve as a prognostic biomarker and therapeutic target for GC.
(© 2024. The Author(s).)

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2019C03031 Key Research and Development Program of Zhejiang Province

Keywords: Gastric cancer; KIAA1429; RASD1; YTHDF2; m6A; mRNA stability

0 (RNA, Messenger)
0 (RNA-Binding Proteins)
K72T3FS567 (Adenosine)
0 (YTHDF2 protein, human)
CLE6G00625 (N-methyladenosine)
0 (VIRMA protein, human)

Date Created: 20240620 Date Completed: 20240620 Latest Revision: 20240623

20240623

PMC11191263

10.1186/s12967-024-05375-5

38902717