Targeting HAUS7 as a therapeutic approach for esophageal squamous cell carcinoma

Abstract

Uncontrolled cell division is a hallmark of cancer, thus targeting deregulated cell cycle molecules with prognostic significance is a promising approach to combat tumorigenesis. My research focuses on HAUS7, a molecule highly relevant to cytokinesis – the terminal phase of the cell cycle, and its association with poor prognostic outcomes of esophageal squamous cell carcinoma (ESCC), shedding light on its significance in ESCC progression. This research targets the interaction of HAUS7 and γ-tubulin using a first brand new peptide HTIP1, which was strategically designed based on my new understanding on the therapeutic mechanism associated with HAUS7 suppression.

Clinical relevance of HAUS7 upregulation was studied in ESCC cohorts from local and public databases. Physiological microtubule-regulating and tumorigenic functions of HAUS7 relative to other HAUS members were investigated in vitro and/or in vivo. Multidisciplinary approaches, which included RNA-sequencing analysis, mass spectrometry, transmission electron microscopy, in silico predictions and modelling, bioinformatics analysis, biochemical methods, cellular assays, immunoassays and in vivo animal models, were employed to decode the mechanism underlying HAUS7 suppression in ESCC. HTIP1 was designed by structure modelling and docking simulation. Its properties, tumor specificity, cancer selectivity, anti-tumor efficacy, off-target effect and mechanism of action were comprehensively evaluated. Patient-derived tumor xenograft (PDX) models were established and used to provide preclinical evidence.

Notably, among HAUS members, HAUS7 was most essential for regulating microtubule dynamics and with high clinical relevance in ESCC, providing new insights into its role in ESCC progression. Its overexpression was correlated with aggressive tumor phenotypes and poor prognosis, both in overall survival and disease-free survival times. Mechanistically, HAUS7 suppression released its unique binding partner γ-tubulin. The free γ-tubulin upon phosphorylation seized LMAN1 and together both of them relocalized to the nucleus. Given the protein-transporting function of LMAN1 at endoplasmic reticulum (ER), its removal from the innate location triggered ER stress and subsequent apoptosis. Capable to perturb HAUS7/γ-tubulin interaction, HTIP1 treatment manifested similar anti-tumor effects like HAUS7 suppression, while demonstrating high tumor specificity, negligible off-target effects and more potent than relevant compounds.

In summary, it was first discovered that a unique physiological function and pathological relevance of HAUS7 among other HAUS members in ESCC. A new therapeutic mechanism was dissected under HAUS7 suppression. It was advanced the understanding of HAUS7 in the context of ESCC tumorigenesis, unveiled a novel therapeutic approach targeting HAUS7/γ-tubulin interaction, and set the stage for the development of potential new drug candidates for ESCC treatment. This invention paved a new strategy to counter ESCC tumorigenesis. By translating the scientific evidence to support further R&D of HTIP1, the ultimate goal is to advance the development of a brand new drug for ESCC treatment.