BMI1 promotes osteosarcoma proliferation and metastasis by repressing the transcription of SIK1.
BMI1 promotes osteosarcoma proliferation and metastasis by repressing the transcription of SIK1.
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DOI：
10.1186/s12935-022-02552-8
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发表时间：
2022-03-27
影响因子：
5.8
通讯作者：
Shen J
中科院分区：
文献类型：
--
作者：
Wang Q;Wu Y;Lin M;Wang G;Liu J;Xie M;Zheng B;Shen C;Shen J
骨肉瘤（osteosarcoma，OS）是最常见的骨恶性肿瘤，目前治疗方法的临床疗效和生存率有待于进一步提高。尽管各种研究表明，骨矿物质I 1蛋白在OS细胞和组织中普遍上调，但其具体作用和潜在机制尚未完全探讨。Western blot检测骨矿物质I 1蛋白在骨肉瘤细胞中的表达。在体外使用CCK-8、集落形成和transwell测定，以及在体内使用异种移植裸鼠中的皮下肿瘤发生和肺转移测定，研究了BMI 1对OS细胞（143 B和U-2 OS细胞系）的增殖和迁移的影响。免疫荧光法检测上皮间质转化相关蛋白的表达。使用ENCODE数据库进行生物信息学分析以预测BMI 1的下游靶标。实时荧光定量PCR检测骨肉瘤细胞中SIK 1 mRNA的表达。染色质免疫沉淀-qPCR（ChIP-qPCR）用于研究OS细胞中SIK 1启动子上BMI 1的推定结合区域处的BMI 1相关、RING 1B相关、H2 AK 119 ub相关和H3 K4 me 3相关DNA的表达。使用体外和体内实验方法，我们发现BMI 1促进OS细胞增殖和转移。肿瘤抑制基因SIK 1被鉴定为OS细胞中BMI 1的直接靶基因。体外实验表明，SIK 1可抑制OS细胞的增殖和迁移。SIK 1的抑制在很大程度上挽救了BMI 1缺陷OS细胞的改变的表型。从机制上讲，我们证明了BMI 1直接与RING 1B复合物中的SIK 1启动子区域结合，以促进组蛋白H2 A在赖氨酸119（H2 AK 119 ub）处的单泛素化，并抑制H3 K4三甲基化（H3 K4 me 3），从而抑制SIK 1转录。因此，我们认为BMI 1通过抑制SIK 1促进OS细胞增殖和转移。我们的研究结果揭示了一种新的分子机制，骨矿物质1促进OS的发展，并提供了一个新的潜在的目标OS的治疗。在线版本包含补充材料，可通过10.1186/s12935-022-02552-8获得。
Osteosarcoma (OS) is the most common malignant tumor of bone, and the clinical efficacy of current treatments and associated survival rates need to be further improved by employing novel therapeutic strategies. Although various studies have shown that BMI1 protein is universally upregulated in OS cells and tissues, its specific role and underlying mechanism have not yet been fully explored. Expression of BMI1 protein in OS cells was detected by western blot. The effect of BMI1 on proliferation and migration of OS cells (143B and U-2OS cell lines) was investigated in vitro using CCK-8, colony formation and transwell assays, and in vivo using subcutaneous tumorigenesis and lung metastasis assays in xenograft nude mice. Expression of epithelial–mesenchymal transition (EMT)-associated proteins was detected by immunofluorescence imaging. Bioinformatic analysis was performed using ENCODE databases to predict downstream targets of BMI1. SIK1 mRNA expression in osteosarcoma cells was detected by quantitative real-time reverse transcription PCR (qPCR). Chromatin immunoprecipitation-qPCR (ChIP-qPCR) was used to investigate expression of BMI1-associated, RING1B-associated, H2AK119ub-associated and H3K4me3-associated DNA at the putative binding region of BMI1 on the SIK1 promoter in OS cells. Using both in vitro and in vivo experimental approaches, we found that BMI1 promotes OS cell proliferation and metastasis. The tumor suppressor SIK1 was identified as the direct target gene of BMI1 in OS cells. In vitro experiments demonstrated that SIK1 could inhibit proliferation and migration of OS cells. Inhibition of SIK1 largely rescued the altered phenotypes of BMI1-deficient OS cells. Mechanistically, we demonstrated that BMI1 directly binds to the promoter region of SIK1 in a complex with RING1B to promote monoubiquitination of histone H2A at lysine 119 (H2AK119ub) and inhibit H3K4 trimethylation (H3K4me3), resulting in inhibition of SIK1 transcription. We therefore suggest that BMI1 promotes OS cell proliferation and metastasis by inhibiting SIK1. Our results reveal a novel molecular mechanism of OS development promoted by BMI1 and provides a new potential target for OS treatment. The online version contains supplementary material available at 10.1186/s12935-022-02552-8.
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影响因子：
5
作者：
De Faveri LE;Hurst CD;Roulson JA;Wood H;Sanchez-Carbayo M;Knowles MA;Chapman EJ
通讯作者：
Chapman EJ
影响因子：
64.5
作者：
Benayoun BA;Pollina EA;Ucar D;Mahmoudi S;Karra K;Wong ED;Devarajan K;Daugherty AC;Kundaje AB;Mancini E;Hitz BC;Gupta R;Rando TA;Baker JC;Snyder MP;Cherry JM;Brunet A
通讯作者：
Brunet A
影响因子：
28.2
作者：
Hollstein, Pablo E.;Eichner, Lillian J.;Shaw, Reuben J.
通讯作者：
Shaw, Reuben J.
影响因子：
5.4
作者：
Chen, Jin-Long;Chen, Fang;Liu, Nai-Fu
通讯作者：
Liu, Nai-Fu
影响因子：
16
作者：
Cao, R;Tsukada, Y;Zhang, Y
通讯作者：
Zhang, Y