TY - JOUR
T1 - Protein acyltransferase DHHC3 regulates breast tumor growth, oxidative stress, and senescence
AU - Sharma, Chandan
AU - Wang, Hong Xing
AU - Li, Qinglin
AU - Knoblich, Konstantin
AU - Reisenbichler, Emily S.
AU - Richardson, Andrea L.
AU - Hemler, Martin E.
N1 - Funding Information:
C. Sharma, H-W. Wang, Q. Li, K. Knoblich, and M.E. Hemler received support from NIH grant CA42368. A.L. Richardson received support from Breast Cancer Research Foundation.
Funding Information:
C. Sharma, H-W. Wang, Q. Li, K. Knoblich, and M.E. Hemler received support from NIH grant CA42368. A.L. Richardson received support from Breast Cancer Research Foundation. We acknowledge Fenghui Xu and Viviana Cremasco for help in mouse studies and cell sorting, respectively.
Publisher Copyright:
© 2017 American Association for Cancer Research.
PY - 2017/12/15
Y1 - 2017/12/15
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-17-1536
DO - 10.1158/0008-5472.CAN-17-1536
M3 - Article
C2 - 29055014
AN - SCOPUS:85038418198
VL - 77
SP - 6880
EP - 6890
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 24
ER -