Targeting VPS72 inhibits ACTL6A/MYC axis activity in HCC progression

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Hepatocellular carcinoma (HCC) is a complex disease often driven by genomic alterations.
• The precise role of vacuolar protein sorting 72 homologue (VPS72), a gene identified through copy number variation analysis, in HCC remains unclear.

Purpose of the Study:

• To elucidate the mechanistic role of VPS72 in HCC development and progression.
• To identify VPS72 as a potential therapeutic target for HCC.

Main Methods:

• Genome-wide copy number variation and transcriptome analyses to identify novel HCC-associated genes.
• In vitro and in vivo experiments to assess the functional impact of VPS72.
• Co-immunoprecipitation assays to investigate protein interactions (VPS72, ACTL6A, MYC, TRIM21).
• Adeno-associated virus serotype 8 (AAV8)-mediated short hairpin RNA (shRNA) for VPS72 inhibition.

Main Results:

• VPS72 overexpression accelerates HCC initiation and progression in vitro and in vivo.
• VPS72 interacts with oncoproteins MYC and ACTL6A, promoting ACTL6A/MYC complex formation.
• ACTL6A enhances VPS72 stability by disrupting the TRIM21-VPS72 interaction.
• The ACTL6A/VPS72/MYC axis increases MYC target gene transcription, driving HCC.
• VPS72 inhibition via AAV8-shRNA effectively suppresses HCC progression.

Conclusions:

• The study reveals the molecular mechanism involving ACTL6A, VPS72, and MYC in HCC pathogenesis.
• This pathway represents a promising theoretical basis and therapeutic target for managing HCC.