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 and reduces tumour growth . 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.