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A putative PIWIL/piRNA-OTX2 network: An emerging model for epigenetic regulation of cancer stemness in retinoblastoma

Rupa Roy1, Subbulakshmi Chidambaram1

  • 1Department of Biochemistry and Molecular Biology, Pondicherry University, Puducherry 605014, India.

Biochimica Et Biophysica Acta. Gene Regulatory Mechanisms
|July 22, 2025
PubMed

Insights

The PIWIL/piRNA pathway, specifically PIWIL4, is upregulated in retinoblastoma (RB) and drives cancer stemness by regulating OTX2 expression. Targeting this axis offers new therapeutic strategies for RB and similar cancers.

Area of Science:

  • Oncology
  • Epigenetics
  • Molecular Biology

Background:

  • Retinoblastoma (RB) is a pediatric retinal tumor primarily caused by RB1 loss, with significant epigenetic involvement.
  • PIWIL/piRNA pathways are increasingly recognized for their roles in cancer beyond reproduction.
  • PIWIL4 is upregulated in RB, impacting stemness factors like OTX2, SOX2, and NANOG.

Purpose of the Study:

  • To propose a conceptual framework for the PIWIL/piRNA-OTX2 axis in regulating cancer stem cell (CSC) dynamics in RB.
  • To explore the role of PIWIL4 in epigenetic modifications and transcription factor binding at OTX2 cis-regulatory modules (CRMs).
  • To identify potential therapeutic targets within this axis for RB and other cancers.

Main Methods:

  • Review of previous studies on PIWIL/piRNA pathways in cancer and RB.
  • Analysis of PIWIL4's role in regulating stemness factors and oncogenic signaling.
  • Conceptual modeling of PIWIL/piRNA complexes recruiting epigenetic modifiers.

Main Results:

  • PIWIL4 upregulation in RB disrupts stemness factors, including OTX2.
  • PIWIL/piRNA complexes may target OTX2 CRMs, altering chromatin accessibility and transcription factor binding.
  • Aberrant PIWIL4 dysregulates OTX2, impacting stemness and activating Wnt/β-catenin signaling via TSPAN12, EphA2, and ZNF proteins.

Conclusions:

  • The PIWIL/piRNA-OTX2 axis is a potential regulator of CSC dynamics in RB, linking epigenetics, transcription factors, and differentiation.
  • Targeting this axis may disrupt stemness and oncogenic pathways, offering novel therapeutic strategies.
  • This framework could be applicable to other cancers exhibiting similar molecular mechanisms.
Keywords:
Cancer stemnessCis-regulatory modulesEphA2Epigenetic reprogrammingGlioblastomaOTX2PIWIL/piRNARetinoblastoma

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