In the last funding period, we have successfully completed all three proposed aims. Using nuclear HER2 (ErbB2) as a model, we extended our investigation to nuclear EGFR and much progress has been made. The current competitive renewal proposal is to further investigate the novel functions of nuclear EGFR and molecular mechanism of EGFR trafficking from the cell surface to the nucleus. We previously reported that the EGFR complex recognizes and binds to an AT-rich sequence (ATRS) of cyclin D1 transcription. Later, we demonstrated that EGFR interacts with STAT3 in the nucleus and the EGFR/STAT3 complex recognizes the ATRS and STAT binding sequence of the iNOS promoter and co-regulates the transcription of the iNOS gene. Both cyclin D1 and iNOS contribute to tumor progression raising the possibility that nuclear EGFR may be involved in tumor progression. In support of this, we and others have shown that nuclear EGFR correlates with poor clinical outcomes in breast, ovarian, esophagus, and oral cancers. We showed that nuclear EGFR interacts with PCNA, a well-known nucleus-specific antigen and phosphorylates the chromatin-bound PCNA at Tyr-211 residue resulting in stabilization of active PCNA and stimulation of DNA replication. In addition, we identified several interesting proteins interacting with EGFR in the nucleus including RHA and the SWI/SNF complex. RHA is a DNA-binding protein that recognizes the DNA sequence identical to the ATRS sequence and may be a potential candidate to be a DNA-binding partner of nuclear EGFR, which does not have a DNA-binding domain. SWI/SNF is a protein complex involved in chromatin remodeling. These newly identified EGFR interacting proteins have been shown to play a role in tumor progression. Finally, extending our observation that endocytosis and the nuclear pore complex (NPC) are involved in the nuclear translocation from cell surface for both EGFR and HER2 we have preliminary results to suggest that a retrograde transport mechanism is involved in the trafficking of cell surface EGFR to the nucleus. Thus, we hypothesize that nuclear EGFR contributes to tumor progression through transcriptional upregulation of tumor promoting genes and interacting with critical protein complexes involved in chromatin remodeling. The long-term goal of this proposal is to understand the novel functions of nuclear EGFR and their roles in the tumor progression.
Three specific Aims are proposed:
Specific Aim 1 : Transcriptional regulation and tumor progression of nuclear EGFR;
Specific Aim 2 : Nuclear EGFR and chromatin remodeling complex SWI/SNF in breast tumor development;
Specific Aim 3 : Molecular mechanism of EGFR trafficking from cell surface to nucleus. As EGFR has long been considered a cell surface receptor, its nuclear functions have been overlooked for decades. With increasing evidence of receptor tyrosine kinases in the nucleus and gradual discovery of their nuclear functions and prognostic value of nuclear EGFR in multiple human cancers, the current proposal represents a timely project that addresses the critical but """"""""almost neglected"""""""" issues.
The long-term goal of this proposal is to understand the novel functions of nuclear EGFR and their roles in the tumor progression. With increasing evidence of receptor tyrosine kinases in the nucleus and gradual discovery of their nuclear functions including prognostic value of nuclear EGFR in multiple human cancers, the current proposal represents a timely project that addresses the critical but almost forgotten issues.
|Li, Chia-Wei; Lim, Seung-Oe; Xia, Weiya et al. (2016) Glycosylation and stabilization of programmed death ligand-1 suppresses T-cell activity. Nat Commun 7:12632|
|Chen, Mei-Kuang; Hung, Mien-Chie (2016) Regulation of therapeutic resistance in cancers by receptor tyrosine kinases. Am J Cancer Res 6:827-42|
|Hsu, Ming-Chuan; Hung, Wen-Chun; Yamaguchi, Hirohito et al. (2016) Extracellular PKM2 induces cancer proliferation by activating the EGFR signaling pathway. Am J Cancer Res 6:628-38|
|Hsu, Jennifer L; Hung, Mien-Chie (2016) The role of HER2, EGFR, and other receptor tyrosine kinases in breast cancer. Cancer Metastasis Rev 35:575-588|
|Liu, Yen-Liang; Perillo, Evan P; Liu, Cong et al. (2016) Segmentation of 3D Trajectories Acquired by TSUNAMI Microscope: An Application to EGFR Trafficking. Biophys J 111:2214-2227|
|Lim, Seung-Oe; Li, Chia-Wei; Xia, Weiya et al. (2016) EGFR Signaling Enhances Aerobic Glycolysis in Triple-Negative Breast Cancer Cells to Promote Tumor Growth and Immune Escape. Cancer Res 76:1284-96|
|Ko, How-Wen; Lee, Heng-Huan; Huo, Longfei et al. (2016) GSK3? inactivation promotes the oncogenic functions of EZH2 and enhances methylation of H3K27 in human breast cancers. Oncotarget 7:57131-57144|
|Du, Yi; Yamaguchi, Hirohito; Wei, Yongkun et al. (2016) Blocking c-Met-mediated PARP1 phosphorylation enhances anti-tumor effects of PARP inhibitors. Nat Med 22:194-201|
|Wang, Yan; Hsu, Jung-Mao; Kang, Ya'an et al. (2016) Oncogenic Functions of Gli1 in Pancreatic Adenocarcinoma Are Supported by Its PRMT1-Mediated Methylation. Cancer Res 76:7049-7058|
|Li, Chia-Wei; Xia, Weiya; Lim, Seung-Oe et al. (2016) AKT1 Inhibits Epithelial-to-Mesenchymal Transition in Breast Cancer through Phosphorylation-Dependent Twist1 Degradation. Cancer Res 76:1451-62|
Showing the most recent 10 out of 111 publications