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SATB2 dysregulation generates a novel circular RNA and drives KRAS-like transcriptional reprogramming and

Rebekah Eleazer1,2, Smitha George2, Luke J Shoemaker2

  • 1Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, 40536, USA.

Cell Communication and Signaling : CCS
|June 25, 2026
PubMed
Abstract

Insights

Epigenetic factors, specifically Special AT-rich binding protein 2 (SATB2) and its associated circ3915 RNA, can drive oncogenic transformation in lung cells without DNA mutations, revealing new cancer mechanisms.

Area of Science:

  • * Molecular biology and epigenetics research.
  • * Cancer biology and oncogenesis.
  • * Cellular transformation mechanisms.

Background:

  • * Current cancer models primarily focus on driver DNA mutations, overlooking the role of epigenetic factors in oncogenesis.
  • * The sufficiency of non-genetic mechanisms in initiating malignant transformation remains largely unelucidated.
  • * Special AT-rich binding protein 2 (SATB2) functions as a chromatin organizer, capable of reprogramming gene networks.

Purpose of the Study:

  • * To investigate the role of SATB2 expression and chromatin remodeling in oncogenic transformation of human bronchial lung epithelial cells.
  • * To determine if epigenetic changes, independent of DNA mutations, can trigger cancer development.

Main Methods:

  • * Chronic exposure of human bronchial lung epithelial cells to inorganic arsenic (iAs).
  • * Utilized biochemical, molecular, and phenotypic assays to analyze SATB2 expression and chromatin structure.
  • * Investigated the functional consequences of SATB2 and circ3915 RNA expression on cellular transformation.

Main Results:

  • * SATB2 co-expresses with circ3915 RNA, which translates to a peptide localizing with SATB2.
  • * Ectopic expression of SATB2 or circ3915 rearranged chromatin accessibility and induced oncogenic gene expression patterns (KRAS- and NFE2L2-like).
  • * Induced oncogenic phenotypes and KRAS-like transcriptional programs in lung cells without iAs or driver mutations; SATB2 and circ3915 were co-regulated in human lung tumors.

Conclusions:

  • * Transcriptional programs linked to oncogenic pathways can be activated in differentiated cells without predisposing mutations.
  • * Epigenetic modifications mediated by SATB2 and circ3915 are sufficient to initiate oncogenic transformation.
  • * Highlights the critical role of epigenetic mechanisms in cancer development, independent of genetic mutations.

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