247. TARGETING HAUS7/GAMMA-TUBULIN INTERACTION WITH HTIP1 SUPPRESSES TUMORIGENESIS IN ESOPHAGEAL SQUAMOUS CELL CARCINOMA

Abstract

Abstract Background Uncontrolled cell division is a hallmark of cancer, making targeting deregulated cell cycle molecules with prognostic significance a promising approach to combat tumorigenesis. Our research focuses on HAUS7, a molecule highly relevant to esophageal squamous cell carcinoma (ESCC), and its interaction with gamma-tubulin. We designed a novel peptide, HTIP1, to target this interaction and suppress tumorigenesis. Methods We investigated the clinical relevance of HAUS7 upregulation in ESCC cohorts, studied its physiological microtubule-regulating and tumorigenic functions in vitro and/or in vivo, and employed a multidisciplinary approach to decode the mechanism underlying HAUS7 suppression. HTIP1 was designed by structure modelling and docking simulation. Its properties, cancer selectivity, anti-tumor efficacy, off-target effect and mechanisms of action were comprehensively evaluated. Patient-derived tumor xenograft models were used to provide additional preclinical evidence. Results Our results show that HAUS7 is the most essential HAUS member for regulating microtubule dynamics in ESCC, and its overexpression is correlated with aggressive tumor phenotypes and poor prognosis. Mechanistically, HAUS7 suppression releases gamma-tubulin, which upon phosphorylation, seizes LMAN1 and together they re-localize to the nucleus. The removal of LMAN1 from its innate location triggers endoplasmic reticulum stress and apoptosis. We designed HTIP1 to perturb HAUS7/gamma-tubulin interaction, which demonstrated anti-tumor effects similar to HAUS7 suppression, with high tumor specificity, negligible off-target effects, and more potency than relevant compounds. Conclusions Our findings provide a new strategy to counter tumorigenesis and pave the way for the development of a new drug targeting the HAUS7/gamma-tubulin interaction.