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SOX12 通过调节天冬酰胺合成促进结直肠癌细胞增殖和转移。

SOX12 promotes colorectal cancer cell proliferation and metastasis by regulating asparagine synthesis.

机构信息

State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China.

Department of Psychiatry, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China.

出版信息

Cell Death Dis. 2019 Mar 11;10(3):239. doi: 10.1038/s41419-019-1481-9.

DOI:10.1038/s41419-019-1481-9
PMID:30858360
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6412063/
Abstract

The sex-determining region Y (SRY)-box (SOX) family has a crucial role in carcinogenesis and cancer progression. However, the role of SOX12 and the mechanism by which it is dysregulated in colorectal cancer (CRC) remain unclear. Here we analyzed SOX12 expression patterns in two independent CRC cohorts (cohort I, n = 390; cohort II, n = 363) and found that SOX12 was significantly upregulated in CRC, indicating a poor prognosis in CRC patients. Overexpression of SOX12 promoted CRC cell proliferation and metastasis, whereas downregulation of SOX12 hampered CRC aggressiveness. Mechanistically, SOX12 facilitated asparagine synthesis by transactivating glutaminase (GLS), glutamic oxaloacetic transaminase 2 (GOT2), and asparagine synthetase (ASNS). Downregulation of GLS, GOT2, and ASNS blocked SOX12-mediated CRC cell proliferation and metastasis, whereas ectopic expression of GLS, GOT2, and ASNS attenuated the SOX12 knockdown-induced suppression of CRC progression. In addition, serial deletion, site-directed mutagenesis, luciferase reporter, and chromatin immunoprecipitation (ChIP) assays indicated that hypoxia-inducible factor 1α (HIF-1α) directly binds to the SOX12 promoter and induces SOX12 expression. Administration of L-asparaginase decreased SOX12-mediated tumor growth and metastasis. In human CRC samples, SOX12 expression positively correlated with GLS, GOT2, ASNS, and HIF-1α expression. Based on these results, SOX12 may serve as a prognostic biomarker and L-asparaginase represents a potential novel therapeutic agent for CRC.

摘要

性别决定区 Y（SRY）-盒（SOX）家族在致癌作用和癌症进展中起着关键作用。然而，SOX12 的作用及其在结直肠癌（CRC）中失调的机制尚不清楚。在这里，我们分析了两个独立的 CRC 队列（队列 I，n=390；队列 II，n=363）中 SOX12 的表达模式，发现 SOX12 在 CRC 中显著上调，表明 CRC 患者的预后不良。SOX12 的过表达促进了 CRC 细胞的增殖和转移，而 SOX12 的下调则阻碍了 CRC 的侵袭性。在机制上，SOX12 通过反式激活谷氨酰胺酶（GLS）、谷草转氨酶 2（GOT2）和天冬酰胺合成酶（ASNS）促进天冬酰胺的合成。下调 GLS、GOT2 和 ASNS 阻断了 SOX12 介导的 CRC 细胞增殖和转移，而 GLS、GOT2 和 ASNS 的异位表达则减弱了 SOX12 敲低诱导的 CRC 进展抑制。此外，串联缺失、定点突变、荧光素酶报告基因和染色质免疫沉淀（ChIP）实验表明，缺氧诱导因子 1α（HIF-1α）直接与 SOX12 启动子结合并诱导 SOX12 表达。L-天冬酰胺酶的给药降低了 SOX12 介导的肿瘤生长和转移。在人 CRC 样本中，SOX12 的表达与 GLS、GOT2、ASNS 和 HIF-1α 的表达呈正相关。基于这些结果，SOX12 可能作为一个预后生物标志物，L-天冬酰胺酶可能代表 CRC 的一种潜在新的治疗药物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9141/6412063/6bde7dbaaa3b/41419_2019_1481_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9141/6412063/2458ec9fb2c4/41419_2019_1481_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9141/6412063/8f7415ca379c/41419_2019_1481_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9141/6412063/fc4eb17c4916/41419_2019_1481_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9141/6412063/f933fdc4fb8d/41419_2019_1481_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9141/6412063/4ac2a77257a0/41419_2019_1481_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9141/6412063/0bb734825a9e/41419_2019_1481_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9141/6412063/36c15e07f784/41419_2019_1481_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9141/6412063/6bde7dbaaa3b/41419_2019_1481_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9141/6412063/2458ec9fb2c4/41419_2019_1481_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9141/6412063/8f7415ca379c/41419_2019_1481_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9141/6412063/fc4eb17c4916/41419_2019_1481_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9141/6412063/f933fdc4fb8d/41419_2019_1481_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9141/6412063/4ac2a77257a0/41419_2019_1481_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9141/6412063/0bb734825a9e/41419_2019_1481_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9141/6412063/36c15e07f784/41419_2019_1481_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9141/6412063/6bde7dbaaa3b/41419_2019_1481_Fig8_HTML.jpg

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