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

• Published in: Cell death & disease 2019-03, Vol.10 (3), p.239, Article 239
• Main Authors: Du, Feng, Chen, Jie, Liu, Hao, Cai, Yanhui, Cao, Tianyu, Han, Weili, Yi, Xiaofang, Qian, Meirui, Tian, Dean, Nie, Yongzhan, Wu, Kaichun, Fan, Daiming, Xia, Limin
• Format: Article
• Language: English
• Subjects: 13/105; 13/51; 38/1; 38/44; 38/77; 42/70; 59/5; 631/67/2327; 631/67/322; 64/60; Animals; Antibodies; Asparaginase; Asparaginase - metabolism; Asparagine; Asparagine - biosynthesis; Aspartate-ammonia ligase; Aspartate-Ammonia Ligase - metabolism; Biochemistry; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Biomedical and Life Sciences; Caco-2 Cells; Carcinogenesis; Cell Biology; Cell Culture; Cell growth; Cell Movement - genetics; Cell proliferation; Cell Proliferation - genetics; Chromatin; Clonal deletion; Cohort Studies; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - mortality; Colorectal Neoplasms - pathology; Ectopic expression; Female; Gene Expression Regulation, Neoplastic - genetics; Glutaminase; Glutaminase - metabolism; HCT116 Cells; HT29 Cells; Humans; Hypoxia - metabolism; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxia-inducible factors; Immunology; Immunoprecipitation; L-asparaginase; Life Sciences; Male; Metastases; Metastasis; Mice, Inbred BALB C; Mice, Nude; Neoplasm Metastasis; Prognosis; Site-directed mutagenesis; SOXC Transcription Factors - genetics; SOXC Transcription Factors - metabolism; Transaminase; Transaminases - metabolism; Transplantation, Heterologous; Up-Regulation
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-019-1481-9

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.