AF9 sustains glycolysis in colorectal cancer via H3K9ac-mediated PCK2 and FBP1 transcription.
AF9 sustains glycolysis in colorectal cancer via H3K9ac-mediated PCK2 and FBP1 transcription.
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DOI：
10.1002/ctm2.1352
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发表时间：
2023-08
影响因子：
10.6
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中科院分区：
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各种癌症的肿瘤发生受到表观遗传失调的影响。在591个检查的表观遗传调节因子（ERF）中，基于我们的伤口愈合测定，AF 9显示出对结直肠癌（CRC）恶性肿瘤的显著抑制。然而，AF 9在CRC中的确切作用仍有待探索。为了研究AF 9在CRC中的功能，我们利用小干扰RNA（siRNA）敲低591个ERF的表达。随后，我们进行了伤口愈合试验，以评估细胞增殖和迁移。进行体外和体内测定以阐明AF 9在CRC中的潜在影响。分析临床样本以评估AF 9表达与CRC预后之间的关联。此外，采用氧化偶氮甲烷-葡聚糖硫酸钠（AOM/DSS）诱导的CRC AF 9 IEC-/-小鼠模型来确认AF 9在CRC中的作用。为了鉴定AF 9的靶基因，进行了RNA测序和免疫共沉淀分析。此外，应用生物信息学预测来鉴定靶向AF 9的潜在miRNAs。在检测的591个ERF中，AF 9在CRC中表现出下调，并与CRC患者的生存期延长呈正相关。体外和体内实验证明，去除AF 9可以促进细胞增殖、迁移以及糖酵解。具体地，肠上皮细胞中MLLT 3（AF 9）的敲除显著增加了由AOM/DSS诱导的肿瘤形成。我们还发现miR-145可以靶向AF 9的3′非翻译区，从而抑制AF 9的表达。AF 9的缺失导致肿瘤发生基因的表达减少，包括磷酸烯醇式丙酮酸羧激酶2（PCK 2）和果糖1，6-二磷酸酶1（FBP 1），随后促进葡萄糖消耗和肿瘤发生。AF 9对于PCK 2和FBP 1的上调是必不可少的，并且miR-145/AF 9轴的破坏可以作为开发CRC疗法的潜在靶点。1. AF 9耗竭促进结直肠癌进展。2. miR-145/AF 9轴有望成为潜在的治疗靶点。3. AF 9通过修饰磷酸烯醇丙酮酸羧激酶2（PCK 2）和果糖1，6-二磷酸酶1（FBP 1）的表达来调节糖酵解。4. AF 9通过识别H3 K9 ac与PCK 2和FBP 1相互作用。
The tumourigenesis of various cancers is influenced by epigenetic deregulation. Among 591 epigenetic regulator factors (ERFs) examined, AF9 showed significant inhibition of malignancy in colorectal cancer (CRC) based on our wound healing assays. However, the precise role of AF9 in CRC remains to be explored. To investigate the function of AF9 in CRC, we utilised small interfering RNAs (siRNAs) to knock down the expression of 591 ERFs. Subsequently, we performed wound healing assays to evaluate cell proliferation and migration. In vitro and in vivo assays were conducted to elucidate the potential impact of AF9 in CRC. Clinical samples were analysed to assess the association between AF9 expression and CRC prognosis. Additionally, an Azoxymethane‐Dextran Sodium Sulfate (AOM/DSS) induced CRC AF9IEC‐/‐ mouse model was employed to confirm the role of AF9 in CRC. To identify the target gene of AF9, RNA‐seq and coimmunoprecipitation analyses were performed. Furthermore, bioinformatics prediction was applied to identify potential miRNAs that target AF9. Among the 591 ERFs examined, AF9 exhibited downregulation in CRC and showed a positive correlation with prolonged survival in CRC patients. In vitro and in vivo assays proved that depletion of AF9 could promote cell proliferation, migration as well as glycolysis. Specifically, knockout of MLLT3 (AF9) in intestinal epithelial cells significantly increased tumour formation induced by AOM/DSS. We also identified miR‐145 could target 3′untranslated region of AF9 to suppress AF9 expression. Loss of AF9 led to decreased expression of gluconeogenic genes, including phosphoenolpyruvate carboxykinase 2 (PCK2) and fructose 1,6‐bisphosphatase 1 (FBP1), subsequently promoting glucose consumption and tumourigenesis. AF9 is essential for the upregulation of PCK2 and FBP1, and the disruption of the miR‐145/AF9 axis may serve as a potential target for the development of CRC therapeutics. 1. AF9 depletion facilitated colorectal cancer progression. 2. The miR‐145/AF9 axis holds promise as a potential therapeutic target. 3. AF9 modulated glycolysis by modifying the expression of phosphoenolpyruvate carboxykinase 2 (PCK2) and fructose 1,6‐bisphosphatase 1 (FBP1). 4. AF9 interacts with PCK2 and FBP1 through its recognition of H3K9ac.