Protein Acyltransferase DHHC3 Regulates Breast Tumor Growth, Oxidative Stress, and Senescence

Abstract

DHHC-type protein acyltransferases may regulate the localization, stability, and/or activity of their substrates. In this study, we show that the protein palmitoyltransferase DHHC3 is upregulated in malignant and metastatic human breast cancer. Elevated expression of DHHC3 correlated with diminished patient survival in breast cancer and six other human cancer types. ZDHHC3 ablation in human MDA-MB-231 mammary tumor cell xenografts reduced the sizes of both the primary tumor and metastatic lung colonies. Gene array data and fluorescence dye assays documented increased oxidative stress and senescence in ZDHHC3-ablated cells. ZDHHC3-ablated tumors also showed enhanced recruitment of innate immune cells (antitumor macrophages, natural killer cells) associated with clearance of senescent tumors. These antitumor effects were reversed upon reconstitution with wild-type, but not enzyme-active site-deficient DHHC3. Concomitant ablation of the upregulated oxidative stress protein TXNIP substantially negated the effects of ZDHHC3 depletion on oxidative stress and senescence. Diminished DHHC3-dependent palmitoylation of ERGIC3 protein likely played a key role in TXNIP upregulation. In conclusion, DHHC3-mediated protein palmitoylation supports breast tumor growth by modulating cellular oxidative stress and senescence.

The molecular era of protein S-acylation: spotlight on structure, mechanisms, and dynamics

“…Over the last decade, the expression and activity of various DHHC PATs have been reported to be altered in numerous cancers and the connection between protein S-acylation and cancer has been extensively reviewed (Ducker et al 2004;Greaves and Chamberlain 2014;Yeste-Velasco et al 2014;Tian et al 2015;Sharma et al 2017;Chen et al 2017b;De and Sadhukhan 2018). The most classic example of the link between S-acylation and cancer is the small GTPases Ras, and more specifically H-Ras and N-Ras.…”

Senescent cells: Living or dying is a matter of NK cells

“…NKG2D and DNAM‐1 ligand upregulation is p53‐independent but dependent on the redox state, as doxorubicin and melphalan DDR triggering is based on ROS signaling . Induction of tumor senescence associated to increased oxidative stress has been reported also in breast cancer due to protein acyltransferase dysregulation . The resulting SASP, characterized by the secretion of CCL2, CXCL1, CXCL16, and IL‐8, recruits antitumor “M1‐like” macrophages and NK cells leading to reduced tumor growth …”

“…11 Induction of tumor senescence associated to increased oxidative stress has been reported also in breast cancer due to protein acyltransferase dysregulation. 46 The resulting SASP, characterized by the secretion of CCL2, CXCL1, CXCL16, and IL-8, recruits…”

“…antitumor "M1-like" macrophages and NK cells leading to reduced tumor growth. 46 It should be taken into consideration that the release of NKG2D ligands from the cell surface in their soluble form by proteolytic cleavage plays an important role in tumor cell escape from NKG2Ddependent immune surveillance. 47 Interestingly, it has been demonstrated that genotoxic stress-induced upregulation of ADAM10 expression and soluble MICB secretion are primarily associated with senescent cells.…”

Protein palmitoylation and cancer

“…Cancer links is defined broadly as any literature link between a ZDHHC-family member and a particular cancer, including large-scale and small-scale experimental studies, animal and cell culture studies, and clinical studies, whether functional or correlative. References: ZDHHC2[70,129,130], ZDHHC3[131][132][133], ZDHHC5[87], ZDHHC7[47,134], ZDHHC9[89,92,135,136], ZDHHC11[77,78,137,138], ZDHHC13[49,73], ZDHHC14[82][83][84][85], ZDHHC20[81], ZDHHC23[139]. HPA, Human Protein Atlas (www.proteinatlas.org/).…”