UVA-induced epigenetic regulation of P16INK4a in human epidermal keratinocytes and skin tumor derived cells
UVA-induced epigenetic regulation of P16INK4a in human epidermal keratinocytes and skin tumor derived cells
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DOI：
10.1039/c1pp05197k
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发表时间：
2012-01-01
影响因子：
3.1
通讯作者：
Greinert, Ruediger
中科院分区：
文献类型：
--
作者：
Chen, I-Peng;Henning, Stefan;Greinert, Ruediger
UVA辐射(315-400 nm)已被证明能够诱发DNA损伤，并被认为是一种致癌物质。虽然在UVA照射的细胞和皮肤肿瘤中发现的染色体异常为UVA致癌过程中的遗传参与提供了证据，但它的表观遗传学参与仍然是虚幻的。因此，我们分析了在长期UVA照射的人角质形成细胞中，参与干细胞命运(KLF4，NANOG)、端粒维持(HTERT)和细胞周期控制中的肿瘤抑制(P16(INK4a)，P21(Wafi/Cipi))的5个特定基因的表观遗传学模式。在P16(INK4a)的启动子中检测到允许的组蛋白标记H3K4me3显著减少(经UVA照射10周和15周的细胞分别减少4倍和9倍)，这经常在皮肤癌中发现。这种组蛋白修饰的改变和严重的启动子高甲基化强烈地削弱了P16(INK4a)的转录(分别是10周和15周UVA照射的20倍和40倍)。对皮肤肿瘤来源细胞的分析发现，由于启动子超甲基化和异染色质组蛋白标记H3K9me3和抑制标记H3K27me3的丰富，P16(INK4a)转录同样严重受损。其他基因也检测到了不太明显的UVA诱导的表观遗传学变化，这首次证明UVA能够通过表观遗传DNA和组蛋白变化来修改皮肤癌相关基因的转录。
UVA-radiation (315-400 nm) has been demonstrated to be capable of inducing DNA damage and is regarded as a carcinogen. While chromosomal aberrations found in UVA-irradiated cells and skin tumors provided evidence of the genetic involvement in UVA-carcinogenesis, its epigenetic participation is still illusive. We thus analysed the epigenetic patterns of 5 specific genes that are involved in stem cell fate (KLF4, NANOG), telomere maintenance (hTERT) and tumor suppression in cell cycle control (P16(INK4a), P21(WAFI/CIPI)) in chronically UVA-irradiated HaCaT human keratinocytes. A striking reduction of the permissive histone mark H3K4me3 has been detected in the promoter of P16(INK4a) (4-fold and 9-fold reduction for 10 and 15 weeks UVA-irradiated cells, respectively), which has often been found deregulated in skin cancers. This alteration in histone modification together with a severe promoter hypermethylation strongly impaired the transcription of P16(INK4a) (20-fold and 40-fold for 10 weeks and 15 weeks UVA-irradiation, respectively). Analysis of the skin tumor-derived cells revealed the same severe impairment of the P16(INK4a) transcription attributed to promoter hypermethylation and enrichment of the heterochromatin histone mark H3K9me3 and the repressive mark H3K27me3. Less pronounced UVA-induced epigenetic alterations were also detected for the other genes, demonstrating for the first time that UVA is able to modify transcription of skin cancer associated genes by means of epigenetic DNA and histone alterations.