HACE1 mediates ubiquitin-proteasomal regulation of tumour-associated mTOR Complex 1 (mTORC1)
Mentor Name: Poul Sorensen
Mammalian target of rapamycin complex 1 (mTORC1) is a major regulator of growth and nutrient responses in mammalian cells. Despite its critical roles in both normal cell physiology and cancer biology, the mTORC1 signalling hub remains incompletely understood in terms of how it is controlled in a context-specific manner in tumor cells. In particular, elucidating how mTORC1 contributes to mechanisms by which tumor cells adapt to diverse stresses of the tumor microenvironment is essential for understanding cancer progression.
Recently, we established a new association between HACE1 (HECT domain and ankyrin repeat-containing E3 ubiquitin-protein ligase) E3 activity, a ligase enabling the transfer of ubiquitin, and mTORC1 signalling. HACE1 was first identified as a tumor suppressor gene in sporadic Wilms’ tumor (WT) from analysis of a t(6; 15 )(q21;q21) translocation in a 5-month-old male patient. HACE1 inactivation has since been reported in multiple other tumor types including ovarian carcinoma, non-Hodgkin’s lymphoma, lung carcinoma, pancreatic carcinoma, prostate carcinoma, natural killer cell malignancies, breast cancer and colorectal cancer. Consistent with this, genetic inactivation of Hace1 in mice leads to the development of multiple late-onset tumors, including sarcomas, breast, lung, and other carcinomas, and lymphomas.
Recently, using a combination of cell line and mouse model approaches, we showed that mTORC1 activity is strongly attenuated by HACE1. Our data uncover a previously unknown ubiquitin-dependent molecular mechanism to control mTORC1 activity in tumor cells. Understanding the molecular mechanisms controlling mTORC1 activity in tumor cells is fundamental to developing novel therapeutic strategies targeting mTOR which has broad potential relevance to pediatric cancer biology.
