Inhibition of PHLPP2/cyclin D1 protein translation contributes to the tumor suppressive effect of NFκB2 (p100)
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Jiawei Xu1,3, Yulei Wang1, Xiaohui Hua1, Jiheng Xu1, Zhongxian Tian1, Honglei Jin1, Jingxia Li1, Xue-Ru Wu2, Chuanshu Huang1
1Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987, USA
2Department of Urology, New York University School of Medicine, and Veterans Affairs New York Harbor Healthcare System, Manhattan Campus, New York, NY 10010, USA
3Current address: Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
Chuanshu Huang, email: [email protected]
Keywords: NFκB2 (p100), cyclin D1, PHLPP2, CREB, miR-302d
Received: March 01, 2016 Accepted: March 31, 2016 Published: April 15, 2016
Although the precursor protein of NFκB2 (p100) is thought to act as a tumor suppressor in mammalian cells, the molecular mechanism of its anti-tumor activity is far from clear. Here, we are, for the first time, to report that p100 protein expression was dramatically decreased in bladder cancers of N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN)-treated mice and human patients. Knockdown of p100 in cultured human bladder cancer cells promoted anchorage-independent growth accompanied with elevating abundance of cell-cycle-related proteins and accelerated cell-cycle progression. Above effects could be completely reversed by ectopically expression of p100, but not p52. Mechanistically, p100 inhibited Cyclin D1 protein translation by activating the transcription of LARP7 and its hosted miR-302d, which could directly bind to 3′-UTR of cyclin d1 mRNA and inhibited its protein translation. Furthermore, p100 suppressed the expression of PHLPP2 (PH domain and leucine-rich repeat protein phosphatases 2), thus promoting CREB phosphorylation at Ser133 and subsequently leading to miR-302d transcription. Taken together, our studies not only for the first time establish p100 as a key tumor suppressor of bladder cancer growth, but also identify a novel molecular cascade of PHLPP2/CREB/miR-302d that mediates the tumor suppressive function of p100.
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