Hippo signaling is an emerging tumor suppressor pathway that plays key roles in organ size control and tumorigenesis. Hippo signaling inhibits the transcription co-activator Yes-Associated Protein (YAP), an oncogene amplified in multiple cancers, including hepatocellular carcinoma, colon and ovarian cancer. YAP promotes cell proliferation, epithelial-to-mesenchymal transition (EMT), survival and chemoresistance. Therefore, it is important to understand how YAP activity is regulated for the development of novel cancer therapeutics. We recently discovered that cellular energy level is a novel upstream signal regulating Hippo pathway, through the central metabolic sensors LKB1 and AMP-activated protein kinase (AMPK). Consistently, small molecule activators of AMPK inhibit YAP activity;and YAP is activated in LKB1-deficient cancers. Further understanding this novel signaling mechanism will shed light on how cellular metabolism regulates YAP oncogene.
Our specific aims of this proposal include: (1) To determine the mechanism(s) of metabolic regulation of tight junctions and Hippo signaling. (2) To investigate the roles of tight junction proteins as the central signaling node in regulation of YAP;and to investigate YAP as a downstream oncogenic factor in LKB1-deficient lung cancer. (3) To determine whether activation of AMPK inhibits YAP in vivo;and to target LKB1-deficient lung cancer cells in vitro and in vivo using small molecule inhibitor of YAP-TEAD interaction.

Public Health Relevance

Hippo signaling is involved in organ size control and tumorigenesis through regulation of transcription co-activator and oncogene YAP. We discovered metabolic stress regulates Hippo signaling through LKB1 and AMP-activated protein kinase (AMPK), and the phosphorylation and regulation of cellular tight junction proteins. Understanding this novel signaling mechanism will provide new insights to Hippo signaling and potential therapeutics for LKB1-deficient lung cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA181537-01A1
Application #
8761052
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Watson, Joanna M
Project Start
2014-07-14
Project End
2019-05-31
Budget Start
2014-07-14
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
Zheng, Baohui; Jarugumilli, Gopala K; Chen, Baoen et al. (2016) Chemical Probes to Directly Profile Palmitoleoylation of Proteins. Chembiochem 17:2022-2027
Chen, Baoen; Zheng, Baohui; DeRan, Michael et al. (2016) ZDHHC7-mediated S-palmitoylation of Scribble regulates cell polarity. Nat Chem Biol 12:686-93
Chan, PuiYee; Han, Xiao; Zheng, Baohui et al. (2016) Autopalmitoylation of TEAD proteins regulates transcriptional output of the Hippo pathway. Nat Chem Biol 12:282-9
Bollu, Lakshmi Reddy; Katreddy, Rajashekhara Reddy; Blessing, Alicia Marie et al. (2015) Intracellular activation of EGFR by fatty acid synthase dependent palmitoylation. Oncotarget 6:34992-5003
DeRan, Michael; Yang, Jiayi; Shen, Che-Hung et al. (2014) Energy stress regulates hippo-YAP signaling involving AMPK-mediated regulation of angiomotin-like 1 protein. Cell Rep 9:495-503