A non-canonical role of RCoR2 (REST corepressor 2) has been described in adrenergic neuroblastoma, expanding its established function as a transcriptional corepressor. In this context, RCOR2, driven by a super-enhancer and functionally distinct from its paralogs, can act as a positive regulator that facilitates genomics contacts between core regulatory circuitry (CRC)-bound enhancers and their target core promoters, thereby sustaining gene-expression programs that preserve adrenergic cell identity and promote tumor cell proliferation. This activating behavior challenges the traditional view of RCOR2 as exclusively part of repressive complexes and highlights the functional plasticity of HDAC containing chromatin regulators in pediatric cancers, identifying RCOR2 as a potential therapeutic vulnerability in adrenergic neuroblastoma.[8][9]
