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Intron Retention of DDX39A Driven by SNRPD2 is a Crucial Splicing Axis for Oncogenic MYC/Spliceosome Program in

Cunjie Chang1, Lina Li2, Ling Su1

  • 1School of Pharmacy and Department of Hepatology, the Affiliated Hospital of Hangzhou Normal, University Hangzhou Normal University, Hangzhou, 311121, P. R. China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|July 17, 2024
PubMed

Insights

SNRPD2 (PD2), an upregulated Sm protein in liver cancer (HCC), acts as an oncogene. It drives cancer by sustaining MYC expression, but digitoxin shows cancer-suppressive effects by targeting PD2.

Area of Science:

  • Molecular Biology
  • Oncology
  • Biochemistry

Background:

  • RNA splicing is a critical process regulated by the spliceosome, involving Sm proteins.
  • The role of Sm proteins in hepatocellular carcinoma (HCC) is largely unknown.
  • SNRPD2 (PD2) is identified as a highly upregulated Sm protein in HCC.

Purpose of the Study:

  • To investigate the role of SNRPD2 (PD2) in hepatocellular carcinoma (HCC).
  • To elucidate the molecular mechanism by which PD2 contributes to HCC progression.
  • To explore digitoxin as a potential therapeutic agent targeting PD2 in HCC.

Main Methods:

  • Quantitative analysis of Sm protein expression in HCC.
  • Investigating the interaction of PD2 with DDX39A and HNRNPL.
  • Assessing the effect of PD2 on MYC mRNA nuclear export and protein expression.
  • Evaluating the impact of digitoxin on PD2 interaction and HCC cell viability.

Main Results:

  • SNRPD2 (PD2) is significantly upregulated in HCC and functions as an oncogene.
  • PD2 promotes DDX39A intron retention, sustaining the expression of the short variant (39A_S).
  • 39A_S facilitates MYC mRNA nuclear export, leading to elevated MYC protein levels, which in turn upregulate PD2 transcription, forming a positive feedback loop.
  • Digitoxin directly interacts with PD2 and exhibits significant cancer-suppressive effects in HCC.

Conclusions:

  • A novel oncogenic mechanism involving PD2, DDX39A, and MYC in HCC is revealed.
  • This PD2-mediated positive feedback loop sustains oncogenic signaling in HCC.
  • Digitoxin demonstrates therapeutic potential by disrupting this pathway and suppressing HCC progression.
Keywords:
MYC signalingRNA splicingSm proteinsdigitoxin

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