Identification of anti-tumoral feedback loop between VHLα and hnRNPA2B1 in renal cancer

Area of Science:

• Molecular Biology
• Oncology
• Cancer Research

Background:

• A novel VHLα isoform previously identified negatively modulated hnRNPA2B1 expression, impacting pyruvate kinase transcript splicing in renal cancer.
• The precise regulation and initiation mechanisms of VHLα alternative translation remained largely unknown.

Purpose of the Study:

• To elucidate the CUG-mediated translation initiation of VHLα.
• To investigate the role of hnRNPA2B1 in VHLα alternative translation.
• To identify upstream regulators of hnRNPA2B1 in renal cancer.

Main Methods:

• Investigated CUG-mediated translation initiation of VHLα.
• Assessed the regulatory roles of eukaryotic initiator factor eIF2A and RNA helicase eIF4A.
• Examined hnRNPA2B1's interaction with the VHL transcript.
• Determined the VHLα N-terminal's role in hnRNPA2B1 ubiquitination.
• Identified c-myc's role in regulating hnRNPA2B1 transcription.

Main Results:

• Unraveled the CUG-mediated translation start of VHLα, regulated by eIF2A and eIF4A.
• hnRNPA2B1 was found to promote VHLα alternative translation through direct interaction with the VHL transcript.
• VHLα's N-terminus mediated hnRNPA2B1 ubiquitination at specific lysine residues.
• Aberrant c-myc overexpression was identified as an upstream regulator of hnRNPA2B1 transcription in renal cancer.

Conclusions:

• Established a CUG-mediated translation initiation mechanism for VHLα involving eIF2A and eIF4A.
• Demonstrated a dual role for hnRNPA2B1 in regulating VHLα alternative translation and being regulated by VHLα.
• Identified a novel anti-tumoral feedback loop between VHLα and hnRNPA2B1 in renal cancer, influenced by c-myc signaling.