YTHDF2 and UVB damage response in skin cancer

摘要 皮肤癌是美国和世界范围内最常见的癌症，发病率持续上升22，23。 暴露于来自太阳的紫外线B辐射(UVB)是导致皮肤的主要环境危险因素 癌症。UVB除了造成DNA损伤和增加突变负担外，还会导致 炎性损伤反应，这也可能导致肿瘤的发生。在过去的几十年里，巨大的 在阐明皮肤癌发生机制方面取得了进展，包括 发炎。然而，我们对UVB损伤反应和调控的分子机制的理解 皮肤癌仍然是有限的。最近，我们发现了YTHDF2，一种N6-甲基腺苷(M6A)的新作用。 RNA甲基化阅读器作为自噬靶点，在抑制UVB诱导的炎症和肿瘤生长中发挥作用。 M6A RNA甲基化是真核信使RNA中含量最丰富的内部化学修饰 (MRNA)以及非编码RNA(NcRNA)。M6A修饰调控RNA的命运及其功能， 如RNA稳定性、翻译、核处理和RNA-蛋白质相互作用。在我们初步的指导下 数据和已发表的工作，我们假设YTHDF2，作为m6A阅读器，抑制中波紫外线诱导的损伤 通过转录后调节RNA稳定性的反应和皮肤肿瘤发生。为了检验这一假设， 我们将采用几种新的方法，包括转录组范围的m6A作图、eCLIP-seq和RIP-seq，AS 以及一种皮肤特异性YTHDF2缺失的新小鼠模型。我们的假设将在三个具体的方面进行检验 目标。目标1将确定YTHDF2调节UVB损伤反应和 致瘤性。目标2将确定UVB通过以下途径下调YTHDF2的机制 自噬。目标3将确定抑制YTHDF2在UVB损伤反应和皮肤中的后果 利用角质形成细胞特异性缺失YTHDF2的小鼠的肿瘤发生。成功完成我们的 拟议的工作将极大地扩展我们对UVB损伤响应和监管的知识 YTHDF2和RNA代谢在肿瘤发生中的作用，可能为更好的发展提供新的机会 通过靶向YTHDF2途径预防和治疗皮肤癌的策略。鉴于新兴的关键角色 对于多种癌症的炎症，我们在炎症和YTHDF2方面的工作不仅对皮肤有意义 但也可能适用于其他类型的上皮性肿瘤。

ABSTRACT Skin cancer is the most common cancer in the US and worldwide with a continually increasing incidence 22,23. Exposure to ultraviolet B radiation (UVB) from the sun is the major environmental risk factor causing skin cancer. In addition to causing DNA damage and increased mutation burden, UVB also causes the inflammatory damage response, which can also contribute to tumorigenesis. In the past decades, tremendous progress has been made in elucidating the mechanism of skin cancer development, including the role of inflammation. However, our understanding of the molecular mechanism regulating UVB damage response and skin cancer is still limited. Recently, we have discovered a novel role of YTHDF2, an N6-methyladenosine (m6A) RNA methylation reader, as an autophagy target, in suppressing UVB-induced inflammation and tumor growth. m6A RNA methylation is the most abundant internal chemical modification in eukaryotic messenger RNA (mRNA) as well as non-coding RNA (ncRNA). m6A modification regulates the fate of RNA and its functions, such as RNA stability, translation, nuclear processing, and RNA-protein interactions. Guided by our preliminary data and published work, we hypothesize that YTHDF2, as an m6A reader, suppresses UVB-induced damage response and skin tumorigenesis through post-transcriptionally regulating RNA stability. To test this hypothesis, we will employ several new methods including transcriptome-wide m6A mapping, eCLIP-seq, and RIP-seq, as well as a new mouse model with skin-specific YTHDF2 deletion. Our hypothesis will be tested in three Specific Aims. Aim 1 will determine the mechanism by which YTHDF2 regulates UVB damage response and tumorigenicity. Aim 2 will determine the mechanism by which UVB down-regulates YTHDF2 through autophagy. Aim 3 will determine the consequences of YTHDF2 inhibition in UVB damage response and skin tumorigenesis using mice with keratinocyte-specific deletion of YTHDF2. Successful completion of our proposed work will vastly expand our knowledge on the regulation of UVB damage response and tumorigenesis by YTHDF2 and RNA metabolism, and may provide new opportunities for developing better strategies to prevent and treat skin cancer by targeting the YTHDF2 pathway. Given the emerging critical role of inflammation in multiple cancers, our work here in inflammation and YTHDF2 is not only significant for skin cancer, but may also be applicable to other epithelial tumor types as well.