Open Collections

Turgu, Busra

University of British Columbia

HACE1 (HECT domain and ankyrin repeat-containing E3 ubiquitin-protein ligase) is a member of the HECT E3 ligase family which is attributed with broad tumor suppressor activity, yet its precise mechanisms remain incompletely understood. Rac-related C3 botulinum toxin substrate 1 (RAC1) is the most known target of E3 ligase HACE1. Anti-tumorigenic effect of HACE1 is potentially attributed to targeting RAC1 for degradation, which in turn modulate major pro-oncogenic signaling pathways critical for the tumorigenic processes. My thesis focuses on discovering how HACE1 elicits its anti-tumorigenic effects through RAC1-dependent regulation of pro-oncogenic signaling pathways. My main project unveils a novel association between HACE1 and mammalian target of rapamycin (mTOR) signaling complexes, shedding light on its role in controlling mTOR activity. HACE1 exerts its inhibitory effects on mTORC1 and mTORC2 by promoting ubiquitin-mediated degradation of mTOR in an E3 ligase-dependent manner. Mechanistically, HACE1 binds to and ubiquitinates RAC1 when it is associated with mTOR complexes which leads to proteasomal degradation. This in turn decreases stability of mTOR and reduces mTORC1 and mTORC2 activity. In vivo, Rac1 deletion reverses enhanced mTOR expression in KRasᴳ¹²ᴰ-driven lung tumors of Hace1⁻⧸⁻ mice. Together, our data demonstrates that HACE1 destabilizes mTOR by targeting RAC1 within mTOR-associated complexes. In addition to the mTOR- HACE1 link, I further elucidated the tumor-suppressive capabilities of HACE1 by exploring its role in the context of microenvironmental stress, a key factor in cancer progression. I established a link between HACE1 and hypoxia-inducible factor 1 alpha (HIF1α), a critical stress factor in tumorigenesis through RAC1. An inverse relationship was observed between HACE1 and HIF1α levels in tumors compared to patient-matched normal kidney tissues, highlighting the potential pathophysiological significance of our findings. Together, our data uncover a previously unrecognized function for the HACE1 tumor suppressor in blocking HIF1α accumulation under hypoxia in a RAC1-dependent manner. Collectively, these projects contribute to our understanding of HACE1's role by uncovering a previously unrecognized link between HACE1, its key E3 ligase target RAC1, and oncogenic mTOR and HIF1α signaling, revealing a new ubiquitin-dependent molecular mechanism to control their activity.

Text

2024-03-01

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/87514

Interdisciplinary Oncology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/