Dataset Information

Pharmacological Targeting of DHHC9-Mediated STRN4 Palmitoylation to Suppress YAP-Driven Cancer Metastasis

ABSTRACT: Protein S-palmitoylation, a dynamic and reversible post-translational modification involving the attachment of palmitate to cysteine residues, is a key regulator of protein functionality and cellular signaling. Dysregulation of this modification has emerged as a critical driver of cancer progression, influencing oncogenes and signaling pathways. Among the 23 DHHC palmitoyl transferases responsible for catalyzing S-palmitoylation, aberrant expression of specific members is linked to tumorigenesis and development, underscoring their potential as promising therapeutic targets. However, the cancer-specific roles and substrates of individual DHHC enzymes remain poorly characterized. In this study, we identified DHHC9 as a crucial regulator of adenocarcinoma progression, including colorectal and lung cancers. Functional studies demonstrated that DHHC9 knockdown profoundly inhibited cell migration in vitro and tumor metastasis in vivo. Proteomic analysis revealed STRN4, a core component of the STRIPAK complex, as a DHHC9-specific substrate whose palmitoylation promotes YAP nuclear localization and activates Hippo pathway effectors CCN1, CCN2, and ANKRD1, driving cancer cell migration. Notably, we discovered two small molecules, treprostinil and 10-HCPT, as potent DHHC9 inhibitors that effectively suppressed adenocarcinoma cell migration. Our findings illuminate a pivotal role for DHHC9 in adenocarcinoma metastasis and unveil its potential as a highly promising therapeutic target in cancer treatment, opening new avenues for intervention in palmitoylation-driven malignancies.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

DISEASE(S): Colon Cancer,Lung Carcinoma

SUBMITTER: yang Tian

LAB HEAD: Yang Sun

PROVIDER: PXD060045 | Pride | 2025-09-15

REPOSITORIES: Pride

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Pharmacological Targeting of DHHC9-Mediated STRN4 Palmitoylation to Suppress YAP-Driven Cancer Metastasis.

Tian Yang Y Li Wei W Zhai Qing Q Yu Ying Y Yuan Jiaxin J Ma Yan Y Yang Jingjing J Li Mingyue M Chang Wenwen W Li Wenjing W Huang Keke K Sun Chongran C Zeng Chen C Sun Yingdi Y Gu Jiabao J Zhang Huilin H Li Dameng D Yu Yanan Y Hu Lu L Zhang Peng P Ma Bo B Zheng Junnian J Li Pan P Guo Feng F Sun Yang Y

Journal of cellular and molecular medicine 20250901 17

Protein S-palmitoylation, a dynamic and reversible post-translational modification involving the attachment of palmitate to cysteine residues, is a key regulator of protein functionality and cellular signalling. Dysregulation of this modification has emerged as a critical driver of cancer progression. Among the 23 DHHC palmitoyl transferases responsible for catalysing S-palmitoylation, aberrant expression of specific members is linked to tumorigenesis and development, underscoring their potentia ...[more]

PMID: 40903842

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Project description:Although sex differences in the brain are prevalent, the knowledge about mechanisms underlying sex-related effects on normal and pathological brain functioning is rather poor. It is known that female and male brains differ in size and connectivity. Moreover, those differences are related to neuronal morphology and activity, synapse molecular organization, synaptic plasticity, and molecular signalling pathways. Among different processes assuring proper synapse function are posttranslational modifications, and among them, S-palmitoylation emerges as a crucial mechanism underlying synaptic integrity. Protein S-palmitoylation (S-PALM) refers to the covalent attachment of palmitic acid (C16:0) to cysteine residue(s) via the formation of a thioester bond. Protein S-PALM is governed by a family of PATs, also known as DHHC proteins. Here we focused on the sex-related functional importance of DHHC7 acyltransferase. Under physiological conditions, DHHC7 emerges of particular interest because it palmitoylates various synaptic proteins involved in the regulation of cellular polarity and proliferation as well as in stress and anxiety-related pathology. Moreover, DHHC7 is responsible for S-PALM of sex steroid receptors. Functionally, S-PALM of these receptors regulates their trafficking to the plasma membrane as well as their rapid responses to sex steroid hormones. Using mass spectrometry-based method PANIMoni we identified sex-dependent differences in the S-palmitoylation of synaptic proteins, potentially involved in the regulation of passive membrane properties and excitability (e.g. potassium voltage-gated channels), synaptic transmission (e.g. subunits of glutamate or kainate receptors, voltage-dependent calcium channels) as well as signalling proteins involved in structural plasticity of dendritic spines (e.g. G-proteins and Rab GTPase). Furthermore, to determine a mechanistic source for sex-dependent changes in protein S-palmitoylation we used synaptoneurosomes from DHHC-7 knock-out -/- (DHHC7 KO) female and male mice. Our data showed sex-dependent action of DHHC-7 acyltransferase. Such discovery will facilitate the development of novel and targeted treatments congruous with biological sex.

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