Activation of HIF-1α-mediated DNA methylation enzymes (DNMT3a and TET2) under hypoxic conditions regulates S100A6 transcription to promote lung cancer cell growth and metastasis.

AIM: This research was aimed at investigating the effects of HIF-1α-mediated DNA methylation enzymes (TET2 and DNMT3a) under hypoxic conditions on S100A6 transcription, thereby promoting the growth and metastasis of lung cancer cells.

METHODS: The expression of HIF-1α or S100A6 in lung cancer cells was interfered with under normoxic and hypoxic conditions, and the cell proliferative, migratory, and invasive properties were assessed. The mechanism of HIF-1α-regulated TET2 and DNMT3 effects on S100A6 transcription under hypoxic conditions was further investigated.

RESULTS: Functionally, S100A6 overexpression promoted lung cancer cell proliferation and metastasis. S100A6 overexpression reversed the inhibitory effects of HIF-1α interference on the proliferation and metastasis of lung cancer cells. S100A6 was induced to express in a HIF-1α-dependent manner under hypoxic conditions, and silencing S100A6 or HIF-1α suppressed lung cancer cell proliferation and metastasis under hypoxic conditions. Further TCGA-LUAD database analysis revealed that S100A6 mRNA levels had a negative correlation with methylation levels. Mechanistically, CpG hypomethylation status in the S100A6 promoter HRE had an association with HIF-1α induction. TET2 was enriched in S100A6 promoter region of lung cancer cells under hypoxic conditions, whereas DNMT3a enrichment was reduced in S100A6 promoter region. HIF-1α-mediated S100A6 activation was linked to DNMT3a-associated epigenetic inactivation and TET2 activation.

INNOVATION: The activation of HIF-1α-mediated DNA methylation enzymes under hypoxic conditions regulated S100A6 transcription, thereby promoting lung cancer cell growth and metastasis.

CONCLUSION: In lung cancer progression, hypoxia-induced factor HIF-1α combined with DNA methylation modifications co-regulates S100A6 transcriptional activation and promotes lung cancer cell growth and metastasis.