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YY1 is regulated by ALKBH5-mediated m6A modification and promotes autophagy and cancer progression through targeting

Shijiang Wang1,2,3, Jiangbo Nie1,2,3, Kaiying Xu2,4

  • 1Department of Orthopedic Surgery, The First Affiliated Hospital of Nanchang University, Nanchang 330006, People’s Republic of China.

Aging
|September 19, 2023
PubMed

Insights

The transcription factor YY1 promotes gastric cancer progression by activating autophagy. ALKBH5 and YTHDF1 regulate YY1 stability via m6A modification, offering potential therapeutic targets for gastric cancer.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Epigenetics

Background:

  • The role of transcription factor YY1 in gastric cancer (GC) tumorigenesis and metastasis is multifaceted but not fully elucidated, particularly concerning its regulation of autophagy.
  • Understanding the mechanisms of autophagy regulation in GC is crucial for identifying novel therapeutic strategies.

Purpose of the Study:

  • To investigate the role of YY1 as a key transcription factor in autophagy regulation during gastric cancer progression.
  • To elucidate the regulatory pathway involving ALKBH5, YY1, and ATG4B in GC cell proliferation and invasion.

Main Methods:

  • Western blot, RFP-GFP-LC3 double fluorescence, and transmission electron microscopy (TEM) were used to assess autophagy activity.
  • Methylated RNA immunoprecipitation (MeRIP) was employed to evaluate m6A modification levels of YY1 regulated by ALKBH5.
  • Gain- and loss-of-function assays were performed to study the biological effects of the ALKBH5/YY1/ATG4B axis.

Main Results:

  • YY1 acts as a transcriptional activator of autophagy-related genes, promoting GC cell proliferation and aggressiveness via ATG4B-mediated autophagy.
  • Ectopic expression of ALKBH5 inhibited YY1-induced effects through m6A modification.
  • YTHDF1 enhanced YY1 mRNA stability by recognizing m6A modification.

Conclusions:

  • YY1 is regulated by ALKBH5 and YTHDF1-mediated m6A modification, functioning as an autophagy-dependent driver in gastric cancer progression.
  • The ALKBH5/YY1/ATG4B axis represents a potential therapeutic target for gastric cancer treatment.
Keywords:
ATG4BN6-methyladenosineYY1autophagycancer

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