AbstractAlteration in lipid metabolism is recognized as a hallmark feature of colorectal cancer (CRC). Protein S-palmitoylation plays a critical role in many different cellular processes including protein-lipid interaction. Zinc Finger DHHC-Type Containing 1 (ZDHHC1, also known as ZNF377) belongs to the palmitoyl-transferase ZDHHC family, and is a potential tumor suppressor.

摘要脂质代谢的改变被认为是结直肠癌（CRC）的标志性特征。蛋白质S-棕榈酰化在许多不同的细胞过程中起着关键作用，包括蛋白质-脂质相互作用。含有1（ZDHHC1，也称为ZNF377）的锌指DHHC型属于棕榈酰转移酶ZDHHC家族，是一种潜在的肿瘤抑制因子。

However, our knowledge of the functional roles of ZDHHC1 in CRC is limited. We discovered that ZDHHC1 expression was downregulated in CRC tissues and that low levels of ZDHHC1 were associated with unfavorable prognosis. Functional studies showed that ZDHHC1 inhibited CRC cell proliferation and invasion in vitro and in vivo.

但是，我们对ZDHHC1在CRC中的功能作用的了解是有限的。我们发现ZDHHC1表达在CRC组织中下调，并且低水平的ZDHHC1与不良预后相关。功能研究表明，ZDHHC1在体外和体内抑制CRC细胞的增殖和侵袭。

We also found that lipase G (LIPG) is negatively regulated by ZDHHC1 and plays a key role in CRC cell growth through lipid storage. Additionally, we demonstrated that ZDHHC1 functions as a IGF2BP1-palmitoylating enzyme that induces S-palmitoylation at IGF2BP1-C337, which results in downregulated LIPG expression via m6A modification.

我们还发现脂肪酶G（LIPG）受ZDHHC1负调控，并通过脂质储存在CRC细胞生长中起关键作用。此外，我们证明了ZDHHC1作为IGF2BP1棕榈酰化酶起作用，该酶在IGF2BP1-C337处诱导S-棕榈酰化，从而通过m6A修饰导致LIPG表达下调。

Mechanistic investigations revealed that the ZDHHC1/IGF2BP1/LIPG signaling axis is associated with inhibition of CRC cell growth. Our study uncovers the potential role of ZDHHC1 in CRC, including inhibition of CRC growth by reducing the stability of LIPG mRNA in an m6A dependent-manner by palmitoylation of IGF2BP1..

机理研究表明，ZDHHC1/IGF2BP1/LIPG信号轴与抑制CRC细胞生长有关。我们的研究揭示了ZDHHC1在CRC中的潜在作用，包括通过IGF2BP1的棕榈酰化以m6A依赖性方式降低LIPG mRNA的稳定性来抑制CRC的生长。。

IntroductionColorectal cancer (CRC) ranks as the third most commonly diagnosed cancer and the third most common cause of cancer‐related death. Surgical resection is a primary therapeutic approach in the treatment of CRC [1, 2]; however, stage at diagnosis dictates whether surgery is a feasible option.

引言结直肠癌（CRC）是第三大最常诊断的癌症，也是癌症相关死亡的第三大常见原因。手术切除是治疗CRC的主要治疗方法[1,2]；然而，诊断阶段决定了手术是否可行。

In addition, stage at diagnosis is the most important predictor of survival, with 5 year relative survival ranging from 91% for localized disease to 14% for patients with distant disease [1, 3, 4]. Lipids are essential components of the cell membrane which play a role in regulating cell survival, proliferation, and a range of other cellular processes [5].

此外，诊断阶段是生存率最重要的预测指标，5年相对生存率从局部疾病的91%到远处疾病患者的14%不等[1,3,4]。脂质是细胞膜的重要成分，在调节细胞存活、增殖和一系列其他细胞过程中发挥作用。

Lipids are also important for metabolism [6, 7]. Alterations in lipid metabolism are recognized as a hallmark feature of CRC [8,9,10]. Therefore, clarifying the molecular mechanisms that underlie lipid uptake in CRC cells is likely to be of great importance for the development of targeted therapeutic strategies and improvement in patient prognosis.Protein S-palmitoylation is a reversible post-translational modification (PTM) whereby palmitic acid, a 16-carbon long saturated fatty acid, is covalently attached to proteins at cysteine residues via a labile thioester bond [11, 12].

脂质对代谢也很重要[6，7]。。因此，阐明CRC细胞脂质摄取的分子机制对于制定靶向治疗策略和改善患者预后可能具有重要意义。蛋白质S-棕榈酰化是一种可逆的翻译后修饰（PTM），棕榈酸是一种16碳长的饱和脂肪酸，通过不稳定的硫酯键与半胱氨酸残基处的蛋白质共价连接[11，12]。

Protein S-palmitoylation is known to play critical roles in many different cellular processes including protein-lipid interaction, which is catalyzed by polytopic transmembrane proteins named protein acyltransferases (PATs) with zinc-finger and aspartate–histidine–histidine–cysteine (DHHC) motifs [13,14,15].

已知蛋白质S-棕榈酰化在许多不同的细胞过程中起关键作用，包括蛋白质-脂质相互作用，这是由具有锌指和天冬氨酸-组氨酸-组氨酸-半胱氨酸（DHHC）基序的称为蛋白质酰基转移酶（PATs）的多面体跨膜蛋白催化的[13，14，15]。

There are 23 distinct members of the ZDHHC family in humans, and different ZDHHC enzymes may act as either oncoproteins or tumor suppressors depending on the specific substrate [16, 17]. Zinc Finger DHHC-Type Containing 1 (ZDHHC1, also known as.

人类中有23个不同的ZDHHC家族成员，不同的ZDHHC酶可能作为癌蛋白或肿瘤抑制因子，具体取决于特定的底物[16，17]。锌指DHHC型含有1（ZDHHC1，也称为。

Data availability

数据可用性

All data are available in the main text or the supplementary materials.

所有数据均可在正文或补充材料中找到。

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Download referencesFundingFundingThis work was supported by grants from the Chinese National Natural Science Foundation Grant No. 81572436 (TL). This work was supported by grants from Hubei Provincial Department of Science and Technology Grant No. 2022BEC047 (TL).Author informationAuthor notesThese authors contributed equally: Qun Zhang, Zhouyuan Du.Authors and AffiliationsDepartment of Digestive Surgical Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, ChinaQun Zhang, Zhouyuan Du, Wei Zhou, Wei Li, Qinglin Yang, Haixin Yu & Tao LiuAuthorsQun ZhangView author publicationsYou can also search for this author in.

下载参考文献资助这项工作得到了中国国家自然科学基金81572436（TL）的资助。这项工作得到了湖北省科学技术厅2022BEC047（TL）的资助。作者信息作者注意到这些作者做出了同样的贡献：张群，杜周元。作者和附属机构华中科技大学同济医学院附属协和医院消化外科肿瘤科，武汉，430022，中国张群，杜周元，周伟，李伟，杨庆林，余海欣和刘涛作者张群观点作者出版物您也可以在中搜索这位作者。

PubMed Google ScholarZhouyuan DuView author publicationsYou can also search for this author in

PubMed Google ScholarZhouyuan DuView作者出版物您也可以在

PubMed Google ScholarWei ZhouView author publicationsYou can also search for this author in

PubMed Google ScholarWei ZhouView作者出版物您也可以在

PubMed Google ScholarWei LiView author publicationsYou can also search for this author in

PubMed Google ScholarWei LiView作者出版物您也可以在

PubMed Google ScholarQinglin YangView author publicationsYou can also search for this author in

PubMed Google ScholarQinglin YangView作者出版物您也可以在

PubMed Google ScholarHaixin YuView author publicationsYou can also search for this author in

PubMed Google ScholarHaixin YuView作者出版物您也可以在

PubMed Google ScholarTao LiuView author publicationsYou can also search for this author in

PubMed Google ScholarContributionsTao Liu and Haixin Yu designed the study. Qun Zhang and Zhouyuan Du wrote the manuscript and performed molecular biological experiment. Wei Zhou, Wei Li and Qinglin Yang performed statistical analysis. Haixin Yu and Tao Liu revised the manuscript.

PubMed谷歌学术贡献刘涛和余海欣设计了这项研究。张群和杜周元撰写了手稿并进行了分子生物学实验。Wei Zhou，Wei Li和Qinglin Yang进行了统计分析。余海欣和刘涛修改了手稿。

All authors read and approved the final manuscript.Corresponding authorsCorrespondence to.

所有作者都阅读并批准了最终稿件。。

Haixin Yu or Tao Liu.Ethics declarations

余海欣或刘涛。道德宣言

Competing interests

相互竞争的利益

The authors declare no competing interests.

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Reprints and permissionsAbout this articleCite this articleZhang, Q., Du, Z., Zhou, W. et al. ZDHHC1 downregulates LIPG and inhibits colorectal cancer growth via IGF2BP1 Palmitoylation.

转载和许可本文引用本文Zhang，Q.，Du，Z.，Zhou，W。等人。ZDHHC1通过IGF2BP1棕榈酰化下调LIPG并抑制结直肠癌的生长。

Cancer Gene Ther (2024). https://doi.org/10.1038/s41417-024-00808-1Download citationReceived: 19 May 2024Revised: 05 July 2024Accepted: 10 July 2024Published: 28 July 2024DOI: https://doi.org/10.1038/s41417-024-00808-1Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

癌症基因Ther（2024）。https://doi.org/10.1038/s41417-024-00808-1Download收到引文日期：2024年5月19日修订日期：2024年7月5日接受日期：2024年7月10日发布日期：2024年7月28日OI：https://doi.org/10.1038/s41417-024-00808-1Share本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

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