STARD4 promotes breast cancer cell malignancy

Zhang,Min; Zhang,Min; Xiang,Zhen; Xiang,Zhen; Wang,Feng; Wang,Feng; Shan,Rong; Shan,Rong; Li,Ling; Li,Ling; Chen,Juan; Chen,Juan; Liu,Bao‑An; Liu,Bao‑An; Huang,Juan; Huang,Juan; Sun,Lun‑Quan; Sun,Lun‑Quan; Zhou,Wei‑Bing; Zhou,Wei‑Bing

doi:10.3892/or.2020.7802

STARD4 promotes breast cancer cell malignancy

Authors:
- Min Zhang
- Zhen Xiang
- Feng Wang
- Rong Shan
- Ling Li
- Juan Chen
- Bao‑An Liu
- Juan Huang
- Lun‑Quan Sun
- Wei‑Bing Zhou
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Affiliations: Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China, Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China, Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China, Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China, Hunan Province Clinic Meditech Research Center for Breast Cancer, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
Published online on: October 12, 2020 https://doi.org/10.3892/or.2020.7802
Pages: 2487-2502
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Breast cancer (BRCA) is one of the most common malignancies encountered in women worldwide. Lipid metabolism has been found to be involved in cancer progression. Steroidogenic acute regulatory protein‑related lipid transfer 4 (STARD4) is an important cholesterol transporter involved in the regulatory mechanism of intracellular cholesterol homeostasis. However, to the best of our knowledge, the molecular functions of STARD4 in BRCA are unclear. Immunohistochemical staining and public dataset analysis were performed to investigate the expression levels of STARD4 in BRCA. In the present study, high expression of STARD4 was identified in BRCA samples and higher STARD4 expression was significantly associated with shorter distant metastasis‑free survival time in patients with BRCA, which indicated that STARD4 may be associated with BRCA progression. Cell cytometry system Celigo® analysis, Cell Counting K‑8 assays, flow cytometry, wound healing assays and transwell assays were used to investigate the effects of STARD4 knockdown on proliferation, cell cycle, apoptosis and migration in BRCA cells. Loss‑of‑function assays demonstrated that STARD4 acted as an oncogene to promote proliferation and cell cycle progression, while suppressing apoptosis in BRCA cells in vitro and in vivo. Furthermore, knockdown of STARD4 significantly suppressed BRCA metastasis. To assess the mechanism of action of STARD4, microarray analysis was performed following STARD4 knockdown in MDA‑MB‑231 cells. The data were analyzed in detail using bioinformatics, and a series of genes, including E74 like ETS transcription factor 1, cAMP responsive element binding protein 1 and p21 (RAC1) activated kinase 2, which have been previously reported to be crucial genes implicated in the malignant phenotype of cancer cells, were identified to be regulated by STARD4. Loss‑of function assays demonstrated that knockdown of STARD4 suppressed BRCA proliferation and migration. These findings suggested that STARD4 had an oncogenic effect in human BRCA progression.

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1	Wagner J, Rapsomaniki MA, Chevrier S, Anzeneder T, Langwieder C, Dykgers A, Rees M, Ramaswamy A, Muenst S, Soysal SD, et al: A single-cell atlas of the tumor and immune ecosystem of human breast cancer. Cell. 177:1330–1345 e1318. 2019. View Article : Google Scholar : PubMed/NCBI
2	Ciriello G, Gatza ML, Beck AH, Wilkerson MD, Rhie SK, Pastore A, Zhang H, McLellan M, Yau C, Kandoth C, et al: Comprehensive molecular portraits of invasive lobular breast cancer. Cell. 163:506–519. 2015. View Article : Google Scholar : PubMed/NCBI
3	Jung SY, Rosenzweig M, Sereika SM, Linkov F, Brufsky A and Weissfeld JL: Factors associated with mortality after breast cancer metastasis. Cancer Causes Control. 23:103–112. 2012. View Article : Google Scholar : PubMed/NCBI
4	Li XH, Song JW, Liu JL, Wu S, Wang Ls, Gong Ly and Lin X: Serine-Arginine protein kinase 1 is associated with breast cancer progression and poor patient survival. Med Oncol. 31:832014. View Article : Google Scholar : PubMed/NCBI
5	Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA and Jemal A: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 68:394–424. 2018. View Article : Google Scholar : PubMed/NCBI
6	Zhu J and Thompson CB: Metabolic regulation of cell growth and proliferation. Nat Rev Mol Cell Biol. 20:436–450. 2019. View Article : Google Scholar : PubMed/NCBI
7	Kamphorst JJ and Gottlieb E: Cancer metabolism: Friendly neighbours feed tumour cells. Nature. 536:401–402. 2016. View Article : Google Scholar : PubMed/NCBI
8	Wagner EF and Petruzzelli M: Cancer metabolism: A waste of insulin interference. Nature. 521:430–431. 2015. View Article : Google Scholar : PubMed/NCBI
9	Tasselli L and Chua KF: Cancer: Metabolism in ‘the driver's seat’. Nature. 492:362–363. 2012. View Article : Google Scholar : PubMed/NCBI
10	Cao Y: Adipocyte and lipid metabolism in cancer drug resistance. J Clin Invest. 129:3006–3017. 2019. View Article : Google Scholar : PubMed/NCBI
11	Chang IY, Ohn T, Ko GS, Yoon Y, Kim JW and Yoon SP: Immunolocalization of steroidogenic acute regulatory protein-related lipid transfer (START) domain-containing proteins in the developing cerebellum of normal and hypothyroid rats. J Chem Neuroanat. 43:28–33. 2012. View Article : Google Scholar : PubMed/NCBI
12	Ishikawa T, Hwang K, Lazzarino D and Morris PL: Sertoli cell expression of steroidogenic acute regulatory protein-related lipid transfer 1 and 5 domain-containing proteins and sterol regulatory element binding protein-1 are interleukin-1beta regulated by activation of c-jun n-terminal kinase and cyclooxygenase-2 and cytokine induction. Endocrinology. 146:5100–5111. 2005. View Article : Google Scholar : PubMed/NCBI
13	Clark BJ: The mammalian START domain protein family in lipid transport in health and disease. J Endocrinol. 212:257–275. 2012. View Article : Google Scholar : PubMed/NCBI
14	Soccio RE, Adams RM, Romanowski MJ, Sehayek E, Burley SK and Breslow JL: The cholesterol-regulated starD4 gene encodes a StAR-related lipid transfer protein with two closely related homologues, starD5 and starD6. Proc Natl Acad Sci USA. 99:6943–6948. 2002. View Article : Google Scholar : PubMed/NCBI
15	Alpy F and Tomasetto C: Give lipids a START: The StAR-related lipid transfer (START) domain in mammals. J Cell Sci. 118:2791–2801. 2005. View Article : Google Scholar : PubMed/NCBI
16	Calderon-Dominguez M, Gil G, Medina MA, Pandak WM and Rodríguez-Agudo D: The starD4 subfamily of steroidogenic acute regulatory-related lipid transfer (START) domain proteins: New players in cholesterol metabolism. Int J Biochem Cell Biol. 49:64–68. 2014. View Article : Google Scholar : PubMed/NCBI
17	Riegelhaupt JJ, Waase MP, Garbarino J, Cruz DE and Breslow JL: Targeted disruption of steroidogenic acute regulatory protein D4 leads to modest weight reduction and minor alterations in lipid metabolism. J Lipid Res. 51:1134–1143. 2010. View Article : Google Scholar : PubMed/NCBI
18	Rodriguez-Agudo D, Ren S, Wong E, Marques D, Redford K, Gil G, Hylemon P and Pandak WM: Intracellular cholesterol transporter starD4 binds free cholesterol and increases cholesteryl ester formation. J Lipid Res. 49:1409–1419. 2008. View Article : Google Scholar : PubMed/NCBI
19	Garbarino J, Pan M, Chin HF, Lund FW, Maxfield FR and Breslow JL: STARD4 knockdown in hepG2 cells disrupts cholesterol trafficking associated with the plasma membrane, ER, and ERC. J Lipid Res. 53:2716–2725. 2012. View Article : Google Scholar : PubMed/NCBI
20	Bouhaddou M, DiStefano MS, Riesel EA, Carrasco E, Holzapfel HY, Jones DC, Smith GR, Stern AD, Somani SS, Thompson TV and Birtwistle MR: Drug response consistency in CCLE and CGP. Nature. 540:E9–E10. 2016. View Article : Google Scholar : PubMed/NCBI
21	Dey-Rao R, Smith JR, Chow S and Sinha AA: Differential gene expression analysis in CCLE lesions provides new insights regarding the genetics basis of skin vs. systemic disease. Genomics. 104:144–155. 2014. View Article : Google Scholar : PubMed/NCBI
22	Li T, Fan J, Wang B, Traugh N, Chen Q, Liu JS, Li B and Liu XS: TIMER: A web server for comprehensive analysis of tumor-infiltrating immune cells. Cancer Res. 77:e108–e110. 2017. View Article : Google Scholar : PubMed/NCBI
23	Gyorffy B, Lánczky A and Szállási Z: Implementing an online tool for genome-wide validation of survival-associated biomarkers in ovarian-cancer using microarray data from 1287 patients. Endocr Relat Cancer. 19:197–208. 2012. View Article : Google Scholar : PubMed/NCBI
24	Li K, Ma YB, Zhang Z, Tian YH, Xu XL, He YQ, Xu L, Gao Y, Pan WT and Song WJ: Upregulated IQUB promotes cell proliferation and migration via activating Akt/GSK3beta/beta-catenin signaling pathway in breast cancer. Cancer Med. 7:3875–3888. 2018. View Article : Google Scholar : PubMed/NCBI
25	Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, FitzgibbonsP L, Francis G, Goldstein NS, Hayes M, et al: American society of clinical oncology/college of american pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol. 28:2784–2795. 2010. View Article : Google Scholar : PubMed/NCBI
26	Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, Allred DC, Bartlett JM, Bilous M, Fitzgibbons P, et al: Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American society of clinical oncology/college of American pathologists clinical practice guideline update. J Clin Oncol. 31:3997–4013. 2013. View Article : Google Scholar : PubMed/NCBI
27	Dowsett M, Nielsen TO, A'Hern R, Bartlett J, Coombes RC, Cuzick J, Ellis M, Henry NL, Hugh JC, Lively T, et al: Assessment of Ki67 in breast cancer: Recommendations from the international Ki67 in breast cancer working group. J Natl Cancer Inst. 103:1656–1664. 2011. View Article : Google Scholar : PubMed/NCBI
28	Yang F, Liu H, Zhao J, Ma X and Qi W: POLR1B is upregulated and promotes cell proliferation in non-small cell lung cancer. Oncol Lett. 19:671–680. 2020.PubMed/NCBI
29	Wan X, Kong Z, Chu K, Yi C, Hu J, Qin R, Zhao C, Fu F, Wu H, Li Y and Huang Y: Co-Expression analysis revealed PTCH1-3′UTR promoted cell migration and invasion by activating miR-101-3p/SLC39A6 axis in non-small cell lung cancer: Implicating the novel function of PTCH1. Oncotarget. 9:4798–4813. 2018. View Article : Google Scholar : PubMed/NCBI
30	Cai Z, Sanchez A, Shi Z, Zhang T, Liu M and Zhang D: Activation of toll-like receptor 5 on breast cancer cells by flagellin suppresses cell proliferation and tumor growth. Cancer Res. 71:2466–2475. 2011. View Article : Google Scholar : PubMed/NCBI
31	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
32	Wu L, Wei Y, Zhou WB, Zhang YS, Chen QH, Liu MX, Zhu ZP, Zhou J, Yang LH, Wang HM, et al: Gene expression alterations of human liver cancer cells following borax exposure. Oncol Rep. 42:115–130. 2019.PubMed/NCBI
33	Wang Z, Chen J, Zhong MZ, Huang J, Hu YP, Feng DY, Zhou ZJ, Luo X, Liu ZQ, Jiang WZ and Zhou WB: Overexpression of ANLN contributed to poor prognosis of anthracycline-based chemotherapy in breast cancer patients. Cancer Chemother Pharmacol. 79:535–543. 2017. View Article : Google Scholar : PubMed/NCBI
34	Zhou W, Wang Z, Shen N, Pi W, Jiang W, Huang J, Hu Y, Li X and Sun L: Knockdown of ANLN by lentivirus inhibits cell growth and migration in human breast cancer. Mol Cell Biochem. 398:11–19. 2015. View Article : Google Scholar : PubMed/NCBI
35	Zhou W, Guan X, Wang L, Liao Y and Huang J: P12(CDK2-AP1) inhibits breast cancer cell proliferation and in vivo tumor growth. J Cancer Res Clin Oncol. 138:2085–2093. 2012. View Article : Google Scholar : PubMed/NCBI
36	Gandhi N and Das GM: Metabolic reprogramming in breast cancer and its therapeutic implications. Cells. 26:89019.
37	Davis KE, Neinast MD, Sun K, Skiles WM, Bills JD, Zehr JA, Zeve D, Hahner LD, Cox DW, Gent LM, et al: The sexually dimorphic role of adipose and adipocyte estrogen receptors in modulating adipose tissue expansion, inflammation, and fibrosis. Mol Metab. 2:227–242. 2013. View Article : Google Scholar : PubMed/NCBI
38	Korytowski W, Rodriguez-Agudo D, Pilat A and Girotti AW: StarD4-Mediated translocation of 7-hydroperoxycholesterol to isolated mitochondria: Deleterious effects and implications for steroidogenesis under oxidative stress conditions. Biochem Biophys Res Commun. 392:58–62. 2010. View Article : Google Scholar : PubMed/NCBI
39	Korytowski W, Wawak K, Pabisz P, Schmitt JC, Chadwick AC, Sahoo D and Girotti AW: Impairment of macrophage cholesterol efflux by cholesterol hydroperoxide trafficking: Implications for atherogenesis under oxidative stress. Arterioscler Thromb Vasc Biol. 35:2104–2113. 2015. View Article : Google Scholar : PubMed/NCBI
40	Simigdala N, Gao Q, Pancholi S, Roberg-Larsen H, Zvelebil M, Ribas R, Folkerd E, Thompson A, Bhamra A, Dowsett M and Martin LA: Cholesterol biosynthesis pathway as a novel mechanism of resistance to estrogen deprivation in estrogen receptor-positive breast cancer. Breast Cancer Res. 18:582016. View Article : Google Scholar : PubMed/NCBI
41	Munir MT, Ponce C, Powell CA, Tarafdar K, Yanagita T, Choudhury M, Gollahon LS and Rahman SM: The contribution of cholesterol and epigenetic changes to the pathophysiology of breast cancer. J Steroid Biochem Mol Biol. 183:1–9. 2018. View Article : Google Scholar : PubMed/NCBI
42	He S and Nelson ER: 27-Hydroxycholesterol, an endogenous selective estrogen receptor modulator. Maturitas. 104:29–35. 2017. View Article : Google Scholar : PubMed/NCBI
43	McDonnell DP, Chang CY and Nelson ER: The estrogen receptor as a mediator of the pathological actions of cholesterol in breast cancer. Climacteric. 17:60–65. 2014. View Article : Google Scholar : PubMed/NCBI
44	Iaea DB, Dikiy I, Kiburu I, Eliezer D and Maxfield FR: STARD4 membrane interactions and sterol binding. Biochemistry. 54:4623–4636. 2015. View Article : Google Scholar : PubMed/NCBI
45	Rodriguez-Agudo D, Calderon-Dominguez M, Ren S, Marques D, Redford K, Medina-Torres MA, Hylemon P, Gil G and Pandak WM: Subcellular localization and regulation of starD4 protein in macrophages and fibroblasts. Biochim Biophys Acta. 1811:597–606. 2011. View Article : Google Scholar : PubMed/NCBI
46	Garcia-Bermudez J and Birsoy K: Drugging ACAT1 for cancer therapy. Mol Cell. 64:856–857. 2016. View Article : Google Scholar : PubMed/NCBI
47	Saraon P, Trudel D, Kron K, Dmitromanolakis A, Trachtenberg J, Bapat B, van der Kwast T, Jarvi KA and Diamandis EP: Evaluation and prognostic significance of ACAT1 as a marker of prostate cancer progression. Prostate. 74:372–380. 2014. View Article : Google Scholar : PubMed/NCBI
48	Antalis CJ, Arnold T, Rasool T, Lee B, Buhman KK and Siddiqui RA: High ACAT1 expression in estrogen receptor negative basal-like breast cancer cells is associated with LDL-induced proliferation. Breast Cancer Res Treat. 122:661–670. 2010. View Article : Google Scholar : PubMed/NCBI
49	Oikawa T and Yamada T: Molecular biology of the ets family of transcription factors. Gene. 303:11–34. 2003. View Article : Google Scholar : PubMed/NCBI
50	Xiao XH and He SY: ELF1 activated long non-coding RNA CASC2 inhibits cisplatin resistance of non-small cell lung cancer via the miR-18a/IRF-2 signaling pathway. Eur Rev Med Pharmacol Sci. 24:3130–3142. 2020.PubMed/NCBI
51	Budka JA, Ferris MW, Capone MJ and Hollenhorst PC: Common ELF1 deletion in prostate cancer bolsters oncogenic ETS function, inhibits senescence and promotes docetaxel resistance. Genes Cancer. 9:198–214. 2018. View Article : Google Scholar : PubMed/NCBI
52	Fukushima T, Miyazaki Y, Tsushima H, Tsutsumi C, Taguchi J, Yoshida S, Kuriyama K, Scadden D, Nimer S and Tomonaga M: The level of MEF but not ELF-1 correlates with FAB subtype of acute myeloid leukemia and is low in good prognosis cases. Leukemia Res. 27:387–392. 2003. View Article : Google Scholar
53	Rao M, Zhu Y, Cong X and Li Q: Knockdown of CREB1 inhibits tumor growth of human gastric cancer in vitro and in vivo. Oncol Rep. 37:3361–3368. 2017. View Article : Google Scholar : PubMed/NCBI
54	Sakamoto KM and Frank DA: CREB in the pathophysiology of cancer: Implications for targeting transcription factors for cancer therapy. Clin Cancer Res. 15:2583–2587. 2009. View Article : Google Scholar : PubMed/NCBI
55	Shao Y, Qi Y, Huang Y, Liu Z, Ma Y, Guo X, Jiang S, Sun Z and Ruan Q: Human cytomegalovirus miR-US4-5p promotes apoptosis via downregulation of p21-activated kinase 2 in cultured cells. Mol Med Rep. 16:4171–4178. 2017. View Article : Google Scholar : PubMed/NCBI
56	Eron SJ, Raghupathi K and Hardy JA: Dual site phosphorylation of caspase-7 by PAK2 blocks apoptotic activity by two distinct mechanisms. Structure. 25:27–39. 2017. View Article : Google Scholar : PubMed/NCBI
57	Flate E and Stalvey JR: Motility of select ovarian cancer cell lines: Effect of extra-cellular matrix proteins and the involvement of PAK2. Int J Oncol. 45:1401–1411. 2014. View Article : Google Scholar : PubMed/NCBI
58	Gao C, Ma T, Pang L and Xie R: Activation of P21-activated protein kinase 2 is an independent prognostic predictor for patients with gastric cancer. Diagn Pathol. 9:552014. View Article : Google Scholar : PubMed/NCBI
59	Park J, Kim JM, Park JK, Huang S, Kwak SY, Ryu KA, Kong G, Park J and Koo BS: Association of p21-activated kinase-1 activity with aggressive tumor behavior and poor prognosis of head and neck cancer. Head Neck. 37:953–963. 2015. View Article : Google Scholar : PubMed/NCBI