KLF10 upregulates ACSM3 via the PI3K/Akt signaling pathway to inhibit the malignant progression of melanoma

Zhao,Zhirong; Zhan,Yuanchang; Jing,Li; Zhai,Huali

doi:10.3892/ol.2022.13295

KLF10 upregulates ACSM3 via the PI3K/Akt signaling pathway to inhibit the malignant progression of melanoma

Authors:
- Zhirong Zhao
- Yuanchang Zhan
- Li Jing
- Huali Zhai
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Affiliations: Department of Clinical Laboratory, Xi'an Dian Medical Laboratory Co., Ltd., Xi'an Shaanxi 210016, P.R. China, Department of Clinical Laboratory, Xi'an Aerospace General Hospital, Xi'an, Shaanxi 710000, P.R. China, Department of Clinical Laboratory Jingbian County People's Hospital, Yulin, Shaanxi 718500, P.R. China, Department of Clinical Laboratory, Changan Hospital, Xi'an, Shaanxi 710000, P.R. China
Published online on: April 13, 2022 https://doi.org/10.3892/ol.2022.13295
Article Number: 175
Copyright: © Zhao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Malignant melanoma is a type of skin cancer caused by mutations in the DNA of melanocytes. Melanoma is relatively rare compared with other types of skin tumors, but has a highly aggressive biological behavior and consequently, a poorer prognosis. Therefore, the present study aimed to explore the role and mechanism of Kruppel‑like factor 10 (KLF10) and acyl‑CoA medium‑chain synthetase 3 (ACSM3) in melanoma progression. KLF10 expression in melanoma tissues was predicted using Gene Expression Profiling Interactive Analysis (GEPIA). KLF10 expression in healthy and melanoma cells was also detected using reverse transcription‑quantitative PCR and western blotting. Cell transfection was performed to overexpress KLF10 or silence ACSM3. Cell viability, proliferation, migration, invasion and apoptosis were detected using Cell Counting Kit‑8, colony formation, wound healing, Transwell and TUNEL assays, respectively. The activity of the ACSM3 promoter was detected using a dual‑luciferase reporter assay, and the relationship between KLF10 and ACSM3 was detected using the GEPIA database and chromatin immunoprecipitation (ChIP). The results demonstrated that KLF10 expression was significantly downregulated in melanoma cells, especially in A375 cells. Compared with the Ov‑NC group, KLF10 overexpression significantly inhibited the proliferation, invasion and migration of melanoma cells and promoted their apoptosis. Similar to KLF10, ACSM3 was also downregulated in A375 cells compared with that in the HEM group, and the GEPIA database analysis and ChIP assay results demonstrated that KLF10 expression was positively associated with ACSM3 expression. Furthermore, silencing ACSM3 significantly reversed the effect of KLF10 overexpression on cell proliferation, invasion and migration, and ACSM3 knockdown increased the levels of phosphorylated (p)‑PI3K and p‑Akt compared with the levels in the Ov‑KLF10 + sh‑NC group. Overall, the present study suggested that KLF10 inhibited the proliferation, invasion and migration of melanoma cells by targeting ACSM3 via the PI3K/Akt signaling pathway.

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1	Raimondi S, Suppa M and Gandini S: Melanoma epidemiology and sun exposure. Acta Derm Venereol. 100:adv001362020. View Article : Google Scholar : PubMed/NCBI
2	Situm M, Buljan M, Kolić M and Vučić M: Melanoma-clinical, dermatoscopical, and histopathological morphological characteristics. Acta Dermatovenerol Croat. 22:1–12. 2014.PubMed/NCBI
3	Davis LE, Shalin SC and Tackett AJ: Current state of melanoma diagnosis and treatment. Cancer Biol Ther. 20:1366–1379. 2019. View Article : Google Scholar : PubMed/NCBI
4	Soenksen LR, Kassis T, Conover ST, Marti-Fuster B, Birkenfeld JS, Tucker-Schwartz J, Naseem A, Stavert RR, Kim CC, Senna MM, et al: Using deep learning for dermatologist-level detection of suspicious pigmented skin lesions from wide-field images. Sci Transl Med. 13:eabb36522021. View Article : Google Scholar : PubMed/NCBI
5	Teramoto Y, Keim U, Gesierich A, Schuler G, Fiedler E, Tüting T, Ulrich C, Wollina U, Hassel JC, Gutzmer R, et al: Acral lentiginous melanoma: A skin cancer with unfavourable prognostic features. A study of the German central malignant melanoma registry (CMMR) in 2050 patients. Br J Dermatol. 178:443–451. 2018. View Article : Google Scholar : PubMed/NCBI
6	Longvert C and Saiag P: Melanoma update. Rev Med Interne. 40:178–183. 2019.(In French). View Article : Google Scholar : PubMed/NCBI
7	Turner J and Crossley M: Mammalian Kruppel-like transcription factors: More than just a pretty finger. Trends Biochem Sci. 24:236–240. 1999. View Article : Google Scholar : PubMed/NCBI
8	Chang VH, Chu PY, Peng SL, Mao TL, Shan YS, Hsu CF, Lin CY, Tsai KK, Yu WC and Ch'ang HJ: Kruppel-like factor 10 expression as a prognostic indicator for pancreatic adenocarcinoma. Am J Pathol. 181:423–430. 2012. View Article : Google Scholar : PubMed/NCBI
9	Zhou M, Chen J, Zhang H, Liu H, Yao H, Wang X, Zhang W, Zhao Y and Yang N: KLF10 inhibits cell growth by regulating PTTG1 in multiple myeloma under the regulation of microRNA-106b-5p. Int J Biol Sci. 16:2063–2071. 2020. View Article : Google Scholar : PubMed/NCBI
10	Jin W, Chen BB, Li JY, Zhu H, Huang M, Gu SM, Wang QQ, Chen JY, Yu S, Wu J and Shao ZM: TIEG1 inhibits breast cancer invasion and metastasis by inhibition of epidermal growth factor receptor (EGFR) transcription and the EGFR signaling pathway. Mol Cell Biol. 32:50–63. 2012. View Article : Google Scholar : PubMed/NCBI
11	Zhu Z, Wang D and Shen Y: Loss of ACSM3 confers worsened prognosis and immune exclusion to cutaneous melanoma. J Cancer. 11:6582–6590. 2020. View Article : Google Scholar : PubMed/NCBI
12	Yan L, He Z, Li W, Liu N and Gao S: The overexpression of Acyl-CoA Medium-Chain Synthetase-3 (ACSM3) suppresses the ovarian cancer progression via the inhibition of integrin β1/AKT signaling pathway. Front Oncol. 11:6448402021. View Article : Google Scholar : PubMed/NCBI
13	Ruan HY, Yang C, Tao XM, He J, Wang T, Wang H, Wang C, Jin GZ, Jin HJ and Qin WX: Downregulation of ACSM3 promotes metastasis and predicts poor prognosis in hepatocellular carcinoma. Am J Cancer Res. 7:543–553. 2017.PubMed/NCBI
14	Kim J, Shin S, Subramaniam M, Bruinsma E, Kim TD, Hawse JR, Spelsberg TC and Janknecht R: Histone demethylase JARID1B/KDM5B is a corepressor of TIEG1/KLF10. Biochem Biophys Res Commun. 401:412–416. 2010. View Article : Google Scholar : PubMed/NCBI
15	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
16	Pavri SN, Clune J, Ariyan S and Narayan D: Malignant melanoma: Beyond the basics. Plast Reconstr Surg. 138:330e–340e. 2016. View Article : Google Scholar : PubMed/NCBI
17	Rastrelli M, Tropea S, Rossi CR and Alaibac M: Melanoma: Epidemiology, risk factors, pathogenesis, diagnosis and classification. In Vivo. 28:1005–1011. 2014.PubMed/NCBI
18	Elder DE, Bastian BC, Cree IA, Massi D and Scolyer RA: The 2018 World health organization classification of cutaneous, mucosal, and uveal melanoma: Detailed analysis of 9 distinct subtypes defined by their evolutionary pathway. Arch Pathol Lab Med. 144:500–522. 2020. View Article : Google Scholar : PubMed/NCBI
19	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2020. CA Cancer J Clin. 70:7–30. 2020. View Article : Google Scholar : PubMed/NCBI
20	Namikawa K and Yamazaki N: Targeted therapy and immunotherapy for melanoma in Japan. Curr Treat Options Oncol. 20:72019. View Article : Google Scholar : PubMed/NCBI
21	Jin W, Di G, Li J, Chen Y, Li W, Wu J, Cheng T, Yao M and Shao Z: TIEG1 induces apoptosis through mitochondrial apoptotic pathway and promotes apoptosis induced by homoharringtonine and velcade. FEBS Lett. 581:3826–3832. 2007. View Article : Google Scholar : PubMed/NCBI
22	Baroy T, Kresse SH, Skårn M, Stabell M, Castro R, Lauvrak S, Llombart-Bosch A, Myklebost O and Meza-Zepeda LA: Reexpression of LSAMP inhibits tumor growth in a preclinical osteosarcoma model. Mol Cancer. 13:932014. View Article : Google Scholar : PubMed/NCBI
23	Hsu CF, Sui CL, Wu WC, Wang JJ, Yang DH, Chen YC, Yu WC and Chang HS: Klf10 induces cell apoptosis through modulation of BI-1 expression and Ca2+ homeostasis in estrogen-responding adenocarcinoma cells. Int J Biochem Cell Biol. 43:666–673. 2011. View Article : Google Scholar : PubMed/NCBI
24	Junkova K, Mirchi LF, Chylíková B, Janků M, Šilhavý J, Hüttl M, Marková I, Miklánková D, Včelák J, Malínská H, et al: Hepatic transcriptome profiling reveals lack of Acsm3 expression in polydactylous rats with high-fat diet-induced hypertriglyceridemia and visceral fat accumulation. Nutrients. 13:14622021. View Article : Google Scholar : PubMed/NCBI
25	De Preter V, Arijs I, Windey K, Vanhove W, Vermeire S, Schuit F, Rutgeerts P and Verbeke K: Impaired butyrate oxidation in ulcerative colitis is due to decreased butyrate uptake and a defect in the oxidation pathway. Inflamm Bowel Dis. 18:1127–1136. 2012. View Article : Google Scholar : PubMed/NCBI
26	Gopal R, Selvarasu K, Pandian PP and Ganesan K: Integrative transcriptome analysis of liver cancer profiles identifies upstream regulators and clinical significance of ACSM3 gene expression. Cell Oncol (Dordr). 40:219–233. 2017. View Article : Google Scholar : PubMed/NCBI
27	Xu F, Na L, Li Y and Chen L: Roles of the PI3K/AKT/mTOR signalling pathways in neurodegenerative diseases and tumours. Cell Biosci. 10:542020. View Article : Google Scholar : PubMed/NCBI
28	Chen H, Zhou L, Wu X, Li R, Wen J, Sha J and Wen X: The PI3K/AKT pathway in the pathogenesis of prostate cancer. Front Biosci (Landmark Ed). 21:1084–1091. 2016. View Article : Google Scholar : PubMed/NCBI
29	Yang N, Chen J, Zhang H, Wang X, Yao H, Peng Y and Zhang W: LncRNA OIP5-AS1 loss-induced microRNA-410 accumulation regulates cell proliferation and apoptosis by targeting KLF10 via activating PTEN/PI3K/AKT pathway in multiple myeloma. Cell Death Dis. 8:e29752017. View Article : Google Scholar : PubMed/NCBI
30	Li Z, Hong S and Liu Z: LncRNA LINC00641 predicts prognosis and inhibits bladder cancer progression through miR-197-3p/KLF10/PTEN/PI3K/AKT cascade. Biochem Biophys Res Commun. 503:1825–1829. 2018. View Article : Google Scholar : PubMed/NCBI