Int J Biol Sci 2022; 18(7):3034-3047. doi:10.7150/ijbs.67149 This issue

Research Paper

Downregulation of MTAP promotes Tumor Growth and Metastasis by regulating ODC Activity in Breast Cancer

Ying Zhang1, Tian-Tian Zhang1, Lin Gao2, Ya-Nan Tan3, Yu-Ting Li1, Xiang-Yu Tan1, Tu-Xiong Huang2, Hua-Hui Li1, Feng Bai4, Chang Zou2, Xin-Hai Pei5, Bin-Bin Tan1✉, Li Fu1✉

1. Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pharmacology and International Cancer Center, Shenzhen University Health Science Center, Shenzhen 518060, Guangdong, China.
2. Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong, China.
3. Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen 518053, China.
4. Department of Pathology, Shenzhen University Health Science Center, Shenzhen 518060, Guangdong, China.
5. Department of Anatomy and Histology, Shenzhen University Health Science Center, Shenzhen 518060, Guangdong, China.

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Citation:
Zhang Y, Zhang TT, Gao L, Tan YN, Li YT, Tan XY, Huang TX, Li HH, Bai F, Zou C, Pei XH, Tan BB, Fu L. Downregulation of MTAP promotes Tumor Growth and Metastasis by regulating ODC Activity in Breast Cancer. Int J Biol Sci 2022; 18(7):3034-3047. doi:10.7150/ijbs.67149. Available from https://www.ijbs.com/v18p3034.htm

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Abstract

Graphic abstract

5'-Methylthioadenosine phosphorylase (MTAP) is a key enzyme in the methionine salvage pathway and has been reported to suppress tumorigenesis. The MTAP gene is located at 9p21, a chromosome region often deleted in breast cancer (BC). However, the clinical and biological significance of MTAP in BC is still unclear. Here, we reported that MTAP was frequently downregulated in 41% (35/85) of primary BCs and 89% (8/9) of BC cell lines. Low expression of MTAP was significantly correlated with a poor survival of BC patients (P=0.0334). Functional studies showed that MTAP was able to suppress both in vitro and in vivo tumorigenic ability of BC cells, including migration, invasion, angiogenesis, tumor growth and metastasis in nude mice with orthotopic xenograft tumor of BC. Mechanistically, we found that downregulation of MTAP could increase the polyamine levels by activating ornithine decarboxylase (ODC). By treating the MTAP-repressing BC cells with specific ODC inhibitor Difluoromethylornithine (DFMO) or treating the MTAP-overexpressing BC cells with additional putrescine, metastasis-promoting or -suppressing phenotype of these MTAP-manipulated cells was significantly reversed, respectively. Taken together, our data suggested that MTAP has a critical metastasis-suppressive role by tightly regulating ODC activity in BC cells, which may serve as a prominent novel therapeutic target for advanced breast cancer treatment.

Keywords: ODC, MTAP, Polyamine biosynthesis, Breast cancer, Metastasis