YTHDF2 and UVB damage response in skin cancer

摘要 皮肤癌是美国和全世界最常见的癌症，发病率不断增加22，23。 暴露于来自太阳的紫外线B辐射（UVB）是导致皮肤 癌除了造成DNA损伤和增加突变负担外，UVB还导致 炎症损伤反应，这也可以有助于肿瘤发生。在过去的几十年里， 在阐明皮肤癌发展的机制方面取得了进展，包括 炎症然而，我们对调节UVB损伤反应的分子机制的理解， 皮肤癌仍然有限。最近，我们发现了YTHDF2，一种N6-甲基腺苷（m6A）， RNA甲基化阅读器，作为自噬靶点，抑制UVB诱导的炎症和肿瘤生长。 m6A RNA甲基化是真核生物信使RNA中最丰富的内部化学修饰 RNA（mRNA）和非编码RNA（ncRNA）。m6A修饰调节RNA的命运及其功能， 例如RNA稳定性、翻译、核加工和RNA-蛋白质相互作用。根据我们初步的 数据和已发表的工作，我们假设YTHDF 2，作为一个m6A阅读器，抑制UVB诱导的损伤 通过转录后调节RNA的稳定性来调节免疫应答和皮肤肿瘤的发生。为了验证这个假设， 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， 以及具有皮肤特异性YTHDF 2缺失的新小鼠模型。我们的假设将在三个具体的测试 目标。目的1将确定YTHDF 2调节UVB损伤反应的机制， 致瘤性目的2将确定UVB通过以下途径下调YTHDF 2的机制： 自噬目的3将确定YTHDF 2抑制在UVB损伤反应和皮肤损伤中的后果。 使用角质形成细胞特异性缺失YTHDF 2的小鼠的肿瘤发生。成功完成我们的 拟议的工作将大大扩展我们对UVB损伤反应的调节的知识， 通过YTHDF2和RNA代谢的肿瘤发生，并可能提供新的机会，发展更好的 通过靶向YTHDF2途径预防和治疗皮肤癌的策略。鉴于新出现的关键作用 我们在炎症和YTHDF 2方面的工作不仅对皮肤有意义， 癌症，但也可适用于其他上皮肿瘤类型。

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.