A Study of "Acetylation of spliceosome protein PHF5A modulates stress responses and colorectal carcinogenesis through alternative splicing mediated upregulation of KDM3A", Wang et al

The process utilized by cancer cells for adapting to cellular stress is a key point for carcinogenesis. Alternative pre-mRNA splicing induced post-transcriptional gene expression regulation is one of the pathways for tumors maintaining proliferation rates accompanying the malignant phenotype under stress. However, the protein post-translational modification, especially protein acetylation on pre-mRNA splicing processes under stress is unknown. Here, we uncovered a list of hyperacetylated proteins in the context of acutely reduced Acetyl-CoA levels under nutrient starvation. PHD finger-like domain-containing protein 5A (PHF5A/SF3b14b), a component of U2 snRNPs, can be acetylated at lysine 29 in response to multiple cellular stresses which is dependent on p300. PHF5A acetylation strengthens the interaction among U2 snRNPs and affects global pre-mRNA splicing pattern and extensive gene expression. PHF5A hyperacetylation induced alternative splicing stabilizes KDM3A mRNA and promotes its protein expression. Pathologically, PHF5A K29 hyperacetylation and KDM3A upregulation axis are correlated with poor prognosis of colon cancer patients. Our findings uncovered a novel mechanism of anti-stress pathway that acetylation on PHF5A promotes the cancer cells capacity for stress resistance and consequently contributes to colon carcinogenesis. Raw data for "Acetylation of spliceosome protein PHF5A modulates stress responses and colorectal carcinogenesis through alternative splicing mediated upregulation of KDM3A"

癌细胞适应细胞应激的过程，是肿瘤发生发展的关键环节。应激状态下，由可变前体mRNA剪接所介导的转录后基因表达调控，是肿瘤维持增殖速率、伴随恶性表型的重要途径之一。然而，蛋白质翻译后修饰——尤其是参与应激状态下前体mRNA剪接过程的蛋白质乙酰化修饰——其相关机制仍有待阐明。本研究在营养饥饿导致乙酰辅酶A水平急剧降低的背景中，鉴定出一系列高度乙酰化的蛋白质。含PHD指样结构域的蛋白5A（PHD finger-like domain-containing protein 5A, PHF5A/SF3b14b）是U2小核糖核蛋白颗粒（U2 small nuclear ribonucleoprotein particles, U2 snRNPs）的组分之一，可在多种细胞应激刺激下于赖氨酸29位点发生乙酰化修饰，且该修饰依赖于p300酶。PHF5A的乙酰化修饰可增强U2 snRNPs内部的相互作用，进而影响全基因组范围的前体mRNA剪接模式与广泛的基因表达谱。PHF5A高度乙酰化所诱导的可变剪接可稳定KDM3A mRNA，并促进其蛋白表达。病理层面，PHF5A K29位点高度乙酰化与KDM3A上调构成的信号轴，与结肠癌患者的不良预后显著相关。本研究揭示了一条全新的抗应激通路机制：PHF5A的乙酰化修饰可增强癌细胞的应激抵抗能力，进而促进结直肠癌的发生发展。本研究的原始数据对应论文题为"Acetylation of spliceosome protein PHF5A modulates stress responses and colorectal carcinogenesis through alternative splicing mediated upregulation of KDM3A"