背景:无法正确识别结直肠癌(CRC)病理生理学的复杂性,对开发新药物和靶向治疗方法的进展产生了重大影响。脂质氧化和脂肪酸生物合成过程中的不平衡是CRC发展的重要风险因素。特异性靶向过氧化物酶体增殖物激活受体γ(PPARγ)及其下游反应元件的治疗干预,响应脂质代谢,已经发现促进肿瘤的生长,并在癌症患者中显示出显著的临床优势。
方法:进行了临床CRC样本和广泛的体外和体内实验,以通过一系列生化测定确定ZDHHC6及其下游靶标的作用,分子分析方法和脂质代谢组学测定,等。结果:为了研究ZDHHC6对CRC进展的影响,并确定ZDHHC6是否是调节脂肪酸合成的棕榈酰转移酶,直接棕榈酰化并稳定PPARγ,而这种稳定又激活了ACLY转录相关的代谢途径。在这项研究中,我们证明PPARγ在其DNA结合域(DBD)部分经历棕榈酰化。这种与脂质相关的修饰通过防止PPARγ蛋白的去稳定化来增强其稳定性。因此,棕榈酰化的PPARγ抑制其由溶酶体诱导的降解,并促进其转运到细胞核中。此外,我们已经确定锌指-天冬氨酸-组氨酸-半胱氨酸6(ZDHHC6)是脂肪酸生物合成的关键控制因子。ZDHHC6直接与棕榈酰基相互作用并添加棕榈酰基以在PPARγ的DBD结构域内的Cys-313位点稳定PPARγ。因此,这种棕榈酰化导致ATP柠檬酸裂解酶(ACLY)的表达增加。此外,我们的发现表明,ZDHHC6积极刺激脂肪酸的产生,并在结直肠癌的发展中起作用。然而,在体内试验中,当ZDHHC6的表达被抑制时,我们观察到致癌效应显著降低.重要的是,在CRC,ZDHHC6的高表达与PPARγ的表达呈正相关。此外,ZDHHC6的高表达与CRC的严重程度有关,提示预后不良.
结论:我们发现了脂质生物合成受ZDHHC6控制的机制,包括PPARγ-ACLY在CRC进展中的信号传导。这一发现为通过阻断ZDHHC6作为潜在的治疗方法来靶向脂质合成提供了理由。
BACKGROUND: The failure of proper recognition of the intricate nature of pathophysiology in colorectal cancer (CRC) has a substantial effect on the progress of developing novel medications and targeted therapy approaches. Imbalances in the processes of lipid oxidation and biosynthesis of fatty acids are significant risk factors for the development of CRC. Therapeutic intervention that specifically targets the peroxisome proliferator-activated receptor gamma (PPARγ) and its downstream response element, in response to lipid metabolism, has been found to promote the growth of tumors and has shown significant clinical advantages in cancer patients.
METHODS: Clinical CRC samples and extensive in vitro and in vivo experiments were carried out to determine the role of ZDHHC6 and its downstream targets via a series of biochemical assays, molecular analysis approaches and lipid metabolomics assay, etc. RESULTS: To study the effect of ZDHHC6 on the progression of CRC and identify whether ZDHHC6 is a palmitoyltransferase that regulates fatty acid synthesis, which directly palmitoylates and stabilizes PPARγ, and this stabilization in turn activates the ACLY transcription-related metabolic pathway. In this study, we demonstrate that PPARγ undergoes
palmitoylation in its DNA binding domain (DBD) section. This lipid-related modification enhances the stability of PPARγ protein by preventing its destabilization. As a result, palmitoylated PPARγ inhibits its degradation induced by the lysosome and facilitates its translocation into the nucleus. In addition, we have identified zinc finger-aspartate-histidine-cysteine 6 (ZDHHC6) as a crucial controller of fatty acid biosynthesis. ZDHHC6 directly interacts with and adds palmitoyl groups to stabilize PPARγ at the Cys-313 site within the DBD domain of PPARγ. Consequently, this
palmitoylation leads to an increase in the expression of ATP citrate lyase (ACLY). Furthermore, our findings reveals that ZDHHC6 actively stimulates the production of fatty acids and plays a role in the development of colorectal cancer. However, we have observed a significant reduction in the cancer-causing effects when the expression of ZDHHC6 is inhibited in in vivo trials. Significantly, in CRC, there is a strong positive correlation between the high expression of ZDHHC6 and the expression of PPARγ. Moreover, this high expression of ZDHHC6 is connected with the severity of CRC and is indicative of a poor prognosis.
CONCLUSIONS: We have discovered a mechanism in which lipid biosynthesis is controlled by ZDHHC6 and includes the signaling of PPARγ-ACLY in the advancement of CRC. This finding provides a justification for targeting lipid synthesis by blocking ZDHHC6 as a potential therapeutic approach.