Abstract
Linker histone H1 has traditionally been regarded as a structural scaffold that stabilizes higher-order chromatin organization. Recent evidence, however, indicates that H1 variants are dynamic chromatin regulators with variant-specific functions in cancer. Among them, H1.2, encoded by H1-2 (formerly HIST1H1C), has emerged as a context-dependent regulator of chromatin compaction, DNA damage signaling, transcription, stress adaptation, and cell fate. This review summarizes the structural and post-translational features of H1.2 and examines how these properties contribute to tumor progression, invasion, metastasis, and therapeutic resistance. We focus on H1.2-mediated control of the cell cycle, Polycomb-dependent gene silencing, oncogenic transcriptional programs, genotoxic stress tolerance, redox-metabolic adaptation, apoptosis evasion, epithelial-mesenchymal transition-associated drug tolerance, and immune microenvironment remodeling. We also evaluate H1.2 as a tissue-based or circulating biomarker, a post-translational modification-based functional readout, and a guide for biomarker-driven combination therapy. Although direct pharmacological targeting remains preliminary, isoform-selective modulation and interventions targeting H1.2-associated regulatory pathways may expand its future therapeutic potential in precision oncology.