Melanoma antigen A12 regulates cell cycle via tumor suppressor p21 expression
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Teruki Yanagi1,2, Ko Nagai1, Hiroshi Shimizu2 and Shu-Ichi Matsuzawa1,3
1Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA
2Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
3Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto, Japan
Shu-Ichi Matsuzawa, email: [email protected]
Keywords: MAGEA12, cell cycle, p21, cyclin dependent kinase, ubiquitination
Received: May 09, 2017 Accepted: June 08, 2017 Published: July 22, 2017
Melanoma-associated antigen family A (MAGE-A) is a family of cancer/testis antigens that are expressed in malignant tumors but not in normal tissues other than the testes. MAGE-A12 is a MAGE-A family gene whose tumorigenic function in cancer cells remains unclear. Searches of the Oncomine and NextBio databases revealed that malignant tumors show up-regulation of MAGE-A12 mRNA relative to corresponding normal tissue. In PPC1 primary prostatic carcinoma cells and in HCT116 colorectal cancer cells (wild type and p53-depleted), MAGE-A12 gene knockdown using siRNA or shRNA diminishes cancer cell proliferation as assessed by cellular ATP levels, cell counting, and clonogenic assays. FACS analyses of annexin V-PI staining and DNA content show that MAGE-A12 knockdown causes G2/M arrest and apoptosis. In tumor xenografts of HCT116 cells, conditional knockdown of MAGE-A12 suppresses tumor growth. The depletion of MAGE-A12 leads to the accumulation of tumor suppressor p21 in PPC1, HCT116, and p53-depleted HCT116 cells. Conversely, CDKN1A knockdown partially rescues the viability of PPC1 cells transfected with siRNA targeting MAGE-A12, while p21 overexpression leads to proliferation arrest in PPC-1 cells. Furthermore, exogenous MAGE-A12 expression promotes the ubiquitination of p21. Our findings reveal that MAGE-A12 plays crucial roles in p21 stability and tumor growth, suggesting that MAGE-A12 could provide a novel target for cancer treatment.
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