Acetyl-CoA Carboxylase 1 (ACC1) Affects the Proliferation of Clear Cell Renal Cell Carcinoma (ccRCC) by Regulating Cyclin D1/CDK4
CHENG Jing1)##, NI Yue-Li1)##, AGBANA Yannick Luther1), YUN Fang1), YANG Hui1), ZHAO Lei3), LI Xiao-Yu1), ZHANG Xue-Dan1), ZHANG Qiao1), YANG Zhe2), KUANG Ying-Min3)*, ZHU Yue-Chun1)*
1)Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences,Kunming Medical University, Kunming 650500, China; 2)Department of Pathology,First Affiliated Hospital of Kunming Medical University, Kunming 650032, China; 3)Department of Organ Transplantation,First Affiliated Hospital of Kunming Medical University, Kunming 650032, China
Abstract:Acetyl-CoA carboxylase (ACC) is the rate limiting enzyme of fatty acid synthesis pathway. Studies have shown that ACC1 is implicated in a variety of metabolic diseases and cancer. However, the role and mechanism of action of ACC1 in clear cell renal cell carcinoma (ccRCC) have not been reported. In this study, 786-O and Caki-1 clear cell renal carcinoma cells were used as research objects to investigate the effect of abnormal expression of ACC1 on their proliferation and unravel the underlying mechanism. Red oil-O-staining results showed that the lipid content of 786-O and Caki-1 cells was significantly higher than that of human kidney 2 (HK2) cells. By searching TCGA database, we found that the expression of ACC1 proteins in ccRCC was significantly higher than that in normal renal tissues (P < 0.001). Plus, ACC1 protein expression in all clinical TNM stages was significantly higher than that in normal tissues, and the higher the expression of ACC1, the higher the pathological grade. Furthermore, high expression of ACC1 mRNA is positively correlated with poor prognosis in ccRCC patients. Western blotting analysis showed that the expression of ACC1 in 786-O and Caki-1 cells was significantly higher than that in HK2 cells. The results of red oil-O-staining showed that knocking down ACC1 could significantly reduce the lipid content of 786-O and Caki-1 cells. The results of CCK-8 assays and clonogenicity analysis showed that knocking down ACC1 could significantly reduce the proliferation and colony forming ability of 786-O and Caki-1 cells. Flow cytometry analysis showed that after knocking down ACC1, the cell cycle was blocked at the G0/G1 phase and the expression of Cyclin D1 and CDK4 was inhibited. In conclusion, we found that ACC1 is abnormally overexpressed in ccRCC and it favors proliferation by regulating the expression of Cyclin D1 and CDK4. Therefore, ACC1 is a potential target for the treatment of ccRCC.
[1] Ferlay J, Colombet M, Soerjomataram I, et al. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods[J]. Int J Cancer, 2019, 144(8): 1941-1953
[2] Tosco L, Van Poppel H, Frea B, et al. Survival and impact of clinical prognostic factors in surgically treated metastatic renal cell carcinoma[J]. Eur Urol, 2013, 63(4): 646-652
[3] Shields LBE, Rezazadeh Kalebasty A. Spontaneous regression of delayed pulmonary and mediastinal metastases from clear cell renal cell Carcinoma[J]. Case Rep Oncol, 2020, 13(3): 1285-1294
[4] Tacconi EMC, Tuthill M, Protheroe A. Review of adjuvant therapies in renal cell carcinoma: evidence to date[J]. Onco Targets Ther, 2020, 13: 12301-12316
[5] 高硕泽, 范光锐, 杨恩广, 等. 转移性肾透明细胞癌分子靶向及新型免疫治疗进展[J]. 医学综述(Gao SZ, Fan GR, Yang EG, et al. Progress in molecular targeting and novel immunotherapy for metastatic clear cell renal cell carcinoma[J]. Med Recapit), 2020, 26(20): 4032-4037
[6] Widjaja-Adhi M a K, Golczak M. The molecular aspects of absorption and metabolism of carotenoids and retinoids in vertebrates[J]. Biochim Biophys Acta Mol Cell Biol Lipids, 2020, 1865(11): 158571
[7] Zhang Q, Yang Z, Ni Y, et al. NF-κB and pSTAT3 synergistically drive G6PD overexpression and facilitate sensitivity to G6PD inhibition in ccRCC[J]. Cancer Cell Int, 2020, 20: 483
[8] Wettersten HI, Aboud OA, Lara PN, Jr., et al. Metabolic reprogramming in clear cell renal cell carcinoma[J]. Nat Rev Nephrol, 2017, 13(7): 410-419
[9] Qiu B, Ackerman D, Sanchez DJ, et al. HIF2α-Dependent Lipid Storage Promotes Endoplasmic Reticulum Homeostasis in Clear-Cell Renal Cell Carcinoma[J]. Cancer Discov, 2015, 5(6): 652-667
[10] Ye B, Yin L, Wang Q, et al. ACC1 is overexpressed in liver cancers and contributes to the proliferation of human hepatoma Hep G2 cells and the rat liver cell line BRL 3A[J]. Mol Med Rep, 2019, 19(5): 3431-3440
[11] Guo H, Wang B, Xu K, et al. m(6)A Reader HNRNPA2B1 promotes esophageal cancer progression via up-regulation of ACLY and ACC1[J]. Front Oncol, 2020, 10: 553045-553060
[12] Li EQ, Zhao W, Zhang C, et al. Synthesis and anti-cancer activity of ND-646 and its derivatives as acetyl-CoA carboxylase 1 inhibitors[J]. Eur J Pharm Sci, 2019, 137: 105010
[13] Singh KB, Kim SH, Hahm ER, et al. Prostate cancer chemoprevention by sulforaphane in a preclinical mouse model is associated with inhibition of fatty acid metabolism[J]. Carcinogenesis, 2018, 39(6): 826-837
[14] Koundouros N, Poulogiannis G. Reprogramming of fatty acid metabolism in cancer[J]. Br J Cancer, 2020, 122 (1): 4-22
[15] Vernieri C, Pusceddu S, Fucà G, et al. Impact of systemic and tumor lipid metabolism on everolimus efficacy in advanced pancreatic neuroendocrine tumors (pNETs)[J]. Int J Cancer, 2019, 144(7): 1704-1712
[16] Nelson ME, Lahiri S, Chow JD, et al. Inhibition of hepatic lipogenesis enhances liver tumorigenesis by increasing antioxidant defence and promoting cell survival[J]. Nat Commun, 2017, 8: 14689
[17] Xu LX, Hao LJ, Ma JQ, et al. SIRT3 promotes the invasion and metastasis of cervical cancer cells by regulating fatty acid synthase[J]. Mol Cell Biochem, 2020, 464(1-2): 11-20
[18] Liao T, Wang YJ, Hu JQ, et al. Histone methyltransferase KMT5A gene modulates oncogenesis and lipid metabolism of papillary thyroid cancer in vitro[J]. Oncol Rep, 2018, 39(5): 2185-2192
[19] Tchakarska G, Sola B. The double dealing of cyclin D1[J]. Cell Cycle, 2020, 19(2): 163-178
[20] Liu B, Li X, Sun F, et al. HP-CagA+ regulates the expression of CDK4/CyclinD1 via reg3 to change cell cycle and promotecell proliferation[J]. Int J Mol Sci, 2019, 21(1): 224
[21] Lu C, He Y, Duan J, et al. Expression of Wnt3a in hepatocellular carcinoma and its effects on cell cycle and metastasis[J]. Int J Oncol, 2017, 51(4): 1135-1145
[22] Zhang Q, Yang Z, Han Q, et al. G6PD promotes renal cell carcinoma proliferation through positive feedback regulation of p-STAT3[J]. Oncotarget, 2017, 8(65): 109043-109060
[23] Han Q, Han F, Fan Y, et al. Notch3 is involved in the proliferation of renal cancer cells via regulation of cell cycle progression and HIF-2α[J]. Oncol Lett, 2020, 20(6): 379
[24] Li Y, Xiao X, Chen H, et al. Transcription factor NFYA promotes G1/S cell cycle transition and cell proliferation by transactivating cyclin D1 and CDK4 in clear cell renal cell carcinoma[J]. Am J Cancer Res, 2020, 10(8): 2446-2463