C4orf3 Regulates HIF-1α Degradation Under Hypoxic Conditions and Contributes to the Malignant Phenotype in Small Cell Lung Cancer.

Hypoxia is a critical feature of the tumour microenvironment in small cell lung cancer (SCLC) and contributes to malignant progression through hypoxia-inducible factor 1 alpha (HIF-1α)-mediated transcriptional programs. However, the upstream regulators that maintain HIF-1α stability under hypoxic conditions remain incompletely understood. In this study, we identified the chromosome 4 open reading frame 3 (C4orf3) as a hypoxia-inducible gene and investigated its functional significance in SCLC. C4orf3 expression is upregulated under hypoxic conditions, and its knockdown suppresses cell proliferation, migration, and invasion in vitro and reduces tumour growth in vivo. Mechanistically, C4orf3 depletion decreased HIF-1α protein levels even under chemically induced hypoxia, suggesting that its regulation is independent of the canonical PHD-VHL degradation pathway. Further analysis demonstrated that C4orf3 modulates HIF-1α stability through PIASy-mediated SUMOylation. Clinical relevance was supported by a positive association between C4orf3 and HIF-1α expression in resected SCLC tissues. These findings suggested that C4orf3 functions as a regulator of hypoxic adaptation in SCLC by maintaining HIF-1α stability and may represent a potential therapeutic target in hypoxia-driven tumour progression.