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Circ-ZBTB38 as an oncogenic circular RNA: Mechanisms in disrupting RalGAP complexes and its clinical value in

Wanqi Zhang1, Nan Yang2, Yuekai Wang3

  • 1Department of Plastic & Cosmetic Surgery, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, 400042, China; Department of Teaching and Experimental Center, College of Basic Medical Sciences, Army Medical University (Third Military Medical University), Chongqing, 400038, China.

Biochemical and Biophysical Research Communications
|March 31, 2026
PubMed
Abstract

Insights

Circular RNAs (circRNAs) like circ-ZBTB38 promote melanoma by degrading RALGAP B, disrupting Ral signaling. Targeting circ-ZBTB38 offers a new therapeutic strategy for melanoma patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Circular RNAs (circRNAs) are increasingly recognized for their roles in cancer progression.
  • circRNAs have potential as diagnostic and therapeutic targets in various tumors.
  • The specific function of circ-ZBTB38 in melanoma remains largely unexplored.

Purpose of the Study:

  • To investigate the functional mechanism of circ-ZBTB38 in melanoma.
  • To explore the clinical application value of circ-ZBTB38 in melanoma.
  • To elucidate the circ-ZBTB38/RALGAPB regulatory axis in melanoma.

Main Methods:

  • Bioinformatic screening of differentially expressed circRNAs from the GSE138412 dataset.
  • Validation using circBase, qPCR, Sanger sequencing, and RNase R digestion.
  • Functional assays including gain- and loss-of-function experiments, proliferation, migration, and invasion assays.
  • Mechanistic studies involving RNA pull-down, mass spectrometry, RIP assays, ubiquitination assays, and western blotting.
  • In vivo studies using mouse models and clinical correlation analysis via tissue microarrays.

Main Results:

  • circ-ZBTB38 was identified as an oncogenic circRNA, significantly upregulated in melanoma tissues and cell lines.
  • circ-ZBTB38 overexpression promoted melanoma cell proliferation, migration, and invasion.
  • Mechanistically, circ-ZBTB38 binds to RALGAPB, promoting its ubiquitination and degradation, leading to hyperactivation of Ral signaling.
  • High circ-ZBTB38 expression correlated with poor prognosis in melanoma patients.
  • Inhibition of circ-ZBTB38 in vivo suppressed tumor growth, metastasis, and improved survival in mice.

Conclusions:

  • circ-ZBTB38 acts as an oncogene in melanoma by mediating RALGAPB post-translational degradation and activating Ral signaling.
  • The circ-ZBTB38/RALGAPB axis represents a novel regulatory circuit in melanoma.
  • circ-ZBTB38 is a potential prognostic biomarker and therapeutic target for melanoma.
Keywords:
MelanomaMetastasisRALGAPBRalcircRNA

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