Identification of Smurf2 as an HIF-1α–Degrading E3 Ubiquitin Ligase

Overview

In cancer, hypoxia-inducible factor-1 (HIF-1) signaling promotes vascularization, increasing oxygen supply and facilitating the survival of malignant cells. It is also involved in metabolism alteration, immune evasion, cell invasion, and metastasis. We have determined that SMAD-specific E3 ubiquitin protein ligase 2 (Smurf2) reduces the stability of HIF-1α (the alpha subunit of HIF-1). This discovery of a new mechanism by which HIF-1α is regulated improves the under-standing of HIF-1α modulation in cancer cells and provides a path to the development of methods for targeting HIF-1α signaling in cancer treatment.

Market Opportunity

HIF-1α is overexpressed in a variety of cancers and indicates unfavorable prognosis. Several attempts have been made to therapeutically target HIF-1α by blockading its interaction with HIF-1β, interfering with its DNA binding affinity, disrupting its transcriptional activity, or inhibiting its mRNA and protein expression. But until now, there has been no effective way to therapeutically target HIF-1α signaling in cancer treatment.

Innovation and Meaningful Advantages

HIF-1α plays a critical role in promoting angiogenesis. In a variety of cancers, HIF-1α overexpression contributes to invasiveness and metastasis, as well as to chemo- and radiotherapy resistance. We have determined that Smurf2 reduces the stability of HIF-1α. Evidence shows, for example, that overexpression of Smurf2 is correlated with improved overall survival and disease-free survival of patients with clear cell renal cell cancer.

Our discovery of a new mechanism by which HIF-1α is regulated improves understanding of HIF-1α modulation in cancer cells and provides a path to the development of strategies to therapeutically target HIF-1α signaling in cancer treatment. As HIF-1α plays a key role in blood vessel formation, our discovery also applies to other conditions where boosting HIF signaling in normoxia is therapeutically beneficial in treating disease with angiogenesis deficiency, such as gastrointestinal ulceration and ischemic cardiovascular disease.

Collaboration Opportunity

We are interested in exploring 1) startup opportunities with investors; 2) research collaborations with leading pharmaceutical companies to develop this method of treatment; and 3) licensing opportunities with companies.

Principal Investigator

Wafik El-Deiry, MD, PhD

Mencoff Family University Professor of Medical Science, Professor of Pathology and Laboratory Medicine

Brown University

https://vivo.brown.edu/display/weldeiry

wafik_el-deiry@brown.edu

IP Information

Provisional Application Filed

Publication

Zhao S and El-Deiry W. Identification of Smurf2 as a HIF-1α degrading E3 ubiquitin ligase. Oncotarget. 2021 Sept. 28;12(20):1970-79. doi: 10.18632/oncotarget.2808.1

Contact

Andrew Bond, PhD

Senior Director of Business Development,

andrew_bond@brown.edu

Brown Tech ID 3109