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

Recent findings underscore the critical role of PIWIL/piRNA pathways in cancer, extending their known functions beyond reproductive biology. Retinoblastoma (RB), a rare pediatric retinal tumor, is primarily driven by RB1 gene loss but also involves significant epigenetic alterations. Our previous studies revealed that PIWIL4 is significantly upregulated in RB, and its knockdown disrupts the expression of stemness-associated factors, including OTX2, SOX2, and NANOG. In this review, we have proposed that PIWIL/piRNA complexes might recruit epigenetic modifiers to cis-regulatory modules (CRMs) of the OTX2 gene, modulating chromatin accessibility and transcription factor binding. Aberrant PIWIL4 expression may dysregulate OTX2 expression, impacting stemness-maintaining factors and activating oncogenic pathways, including Wnt/β-catenin signaling, mediated by TSPAN12, EphA2, and ZNF proteins. This conceptual framework positions the PIWIL/piRNA-OTX2 axis as a potential regulator of CSC dynamics, linking it to epigenetic modifications, transcription factor interactions, and neuronal differentiation in RB. Targeting this axis could disrupt stemness-associated pathways and oncogenic signaling, offering new therapeutic strategies to mitigate tumor progression and recurrence in RB and other cancers with similar molecular mechanisms.