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Yin Yang 1 promotes mTORC2-mediated AKT phosphorylation.

ABSTRACT: Yin Yang 1 (YY1) regulates both gene expression and protein modifications, and has shown a proliferative role in cancers. In this study, we demonstrate that YY1 promotes AKT phosphorylation at S473, a marker of AKT activation. YY1 expression positively correlated with AKT(S473) phosphorylation in a tissue microarray and cultured cells of breast cancer, but negatively associated with the distant metastasis-free survival of 166 breast cancer patients. YY1 promotes AKT phosphorylation at S473 through direct interaction with AKT, and the AKT-binding site is mapped to the residues G201-S226 on YY1. These residues are also involved in YY1 interaction with Mdm2, Ezh2, and E1A, and thus are designated as the oncogene protein binding (OPB) domain. YY1-promoted AKT phosphorylation relies on the OPB domain but is independent of either transcriptional activity of YY1 or the activity of phosphoinositide-3-kinases. We also determine that YY1-promoted mTORC2 access to AKT leads to its phosphorylation at S473. Importantly, a peptide based on the OPB domain blocks YY1 interaction with AKT and reduces AKT phosphorylation and cell proliferation. Thus, we demonstrate for the first time that YY1 promotes mTORC2-mediated AKT activation and disrupting YY1-AKT interaction by OPB domain-based peptide may represent a potential strategy for cancer therapy.

SUBMITTER: Zhang Q

PROVIDER: S-EPMC5007621 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Yin Yang 1 promotes mTORC2-mediated AKT phosphorylation.

Zhang Qiang Q Wan Meimei M Shi Jinming J Horita David A DA Miller Lance D LD Kute Timothy E TE Kridel Steven J SJ Kulik George G Sui Guangchao G

Journal of molecular cell biology 20160113 3

Yin Yang 1 (YY1) regulates both gene expression and protein modifications, and has shown a proliferative role in cancers. In this study, we demonstrate that YY1 promotes AKT phosphorylation at S473, a marker of AKT activation. YY1 expression positively correlated with AKT(S473) phosphorylation in a tissue microarray and cultured cells of breast cancer, but negatively associated with the distant metastasis-free survival of 166 breast cancer patients. YY1 promotes AKT phosphorylation at S473 throu ...[more]

PMID: 26762111

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Project description:Cisplatin is still one of the first-line drugs for chemotherapy of head and neck squamous cell carcinoma (HNSCC) and shows a survival advantage for HNSCC. However, a substantial proportion of HNSCC eventually becomes resistance to cisplatin and the underlying mechanisms remain to be fully understood. Yin Yang 1 (YY1) is a multifunctional protein regulating both gene transcription and protein modifications and also plays a role in chemotherapy resistance. Here, we reported that knockdown of YY1 by lentivirus-mediated short hairpin RNA or tetracycline-inducible short hairpin RNA enhanced cisplatin-induced apoptosis and inhibition of cell proliferation, migration and invasion in the HNSCC cell lines, and inhibition of the xenograft tumor growth. The underlying mechanisms were revealed that knockdown of YY1 downregulated both S473 and T308 phosphorylation of AKT (protein kinase B), which was mainly responsible for cisplatin resistance, whereas overexpression of YY1 upregulated both S473 and T308 phosphorylation. Cisplatin upregulated YY1 mRNA and protein expression and both S473 and T308 phosphorylation of AKT. In the presence of cisplatin, knockdown of YY1 not only blocked cisplatin-induced increase in S473 and T308 phosphorylation of AKT, but still downregulated T308 phosphorylation. Moreover, protein phosphatase 2A (PP2A) antagonist, okadaic acid, upregulated T308, but not S473, phosphorylation, and simultaneously abolished YY1 knockdown-mediated enhancement of cisplatin-induced inhibition of cell proliferation. In addition, knockdown of YY1 promoted PP2A activity through upregulating mRNA and protein expressions of PP2A catalytic subunit alpha (PPP2CA) through the binding of YY1 in the promoter of PPP2CA. Conversely, activating PP2A by forskolin also promoted YY1 degradation and subsequently inhibited T308 phosphorylation. These results suggested that knockdown of YY1 enhanced anticancer effects of cisplatin through PP2A mediating T308 dephosphorylation of AKT, and that targeting YY1 or PP2A would enhance the efficiency of cisplatin chemotherapy in treatment of HNSCC.

Dataset Information

Yin Yang 1 promotes mTORC2-mediated AKT phosphorylation.

Publications

Yin Yang 1 promotes mTORC2-mediated AKT phosphorylation.

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