Kidney cancer is a deadly disease despite the emergence of new treatments. Inactivation of the VHL tumor suppressor gene plays a causal role in the pathogenesis of clear cell renal carcinomas (ccRCC), a pathological subtype that accounts for the majority of kidney cancer. However, the tumor suppressing mechanism(s) of pVHL remains incompletely understood. Loss of functions of pVHL leads to constitutive activation of HIF, which was critical for tumor formation. In clinic, anti-angiogenesis drugs that partially block the activated HIF pathway have shown positive but transient clinical activity against ccRCC. Although HIF activation is critical for formation and maintenance of kidney cancer, it alone is not enough to cause ccRCC. It was recently discovered that pVHL negatively regulates the activity of EGFR, a receptor tyrosine kinase that is oncogenic when abnormally activated in many cancers. This proposal will investigate how pVHL antagonizes EGFR through multiple mechanisms: a) promoting c-Cbl-independent poly-ubiquitylation and degradation of activated EGFR;b) affecting EGFR signaling transcriptionally by suppressing JARID1C to maintain the overall H3K4Me3 level (H3K4Me3 is critical for active gene transcription);and c) maintaining the sensitivity of EGFR to its inhibitors in VHL+/+ ccRCC cells through an EGFR phosphatase. The proposed studies will uncover and elucidate new tumor-suppressing functions of pVHL. It will also shed light on the tumor-suppressive function of JARID1C, a cancer gene recently identified in ccRCC, and reveal its effect on EGFR signaling. Finally, this study will also provide insights as to why VHL-defective ccRCC tumors are resistant to EGFR inhibitors (EGFRi). Such knowledge can lead to ways to transform EGFRi into effective therapeutics against these tumors.)

Public Health Relevance

Kidney cancer is a deadly disease that requires effective management. Inactivation of the VHL tumor suppressor gene plays a causal role in the pathogenesis of the majority of kidney cancer but its tumor suppressing mechanism(s) remains incompletely understood. The proposed study of HIF-dependent and HIF-independent tumor suppressor functions of pVHL will provide detailed mechanistic understanding of how pVHL works and the knowledge might provide new ways of therapeutic intervention for kidney cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA155015-03
Application #
8641328
Study Section
Special Emphasis Panel (ZRG1-CE-M (09))
Program Officer
Salnikow, Konstantin
Project Start
2012-05-01
Project End
2017-03-31
Budget Start
2014-05-01
Budget End
2015-03-31
Support Year
3
Fiscal Year
2014
Total Cost
$317,517
Indirect Cost
$112,667
Name
Thomas Jefferson University
Department
Pathology
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Cai, Weijia; Yang, Haifeng (2016) The structure and regulation of Cullin 2 based E3 ubiquitin ligases and their biological functions. Cell Div 11:7
Liao, Lili; Testa, Joseph R; Yang, Haifeng (2015) The roles of chromatin-remodelers and epigenetic modifiers in kidney cancer. Cancer Genet 208:206-14
Zhang, Ting; Niu, Xiaohua; Liao, Lili et al. (2013) The contributions of HIF-target genes to tumor growth in RCC. PLoS One 8:e80544