Targeting sine oculis homeoprotein 1 (SIX1) - A review of oncogenic roles and potential natural product therapeutics

Sep 21, 2026

Uploaded by Noah

Sine oculis homeoprotein 1 (SIX1), a homeodomain transcription factor within the SIX family, is strongly linked to tumorigenesis, cancer progression, and prognostic evaluation. Originally identified for essential functions in embryonic development, SIX1 has re-emerged as a key factor across many mammalian cancers. Evidence over the past two decades connects SIX1 to diverse oncogenic events, including altered cellular metabolism and enhanced malignant behavior. This review summarizes SIX1’s roles in normal development and oncogenic mechanisms, highlighting its value as a therapeutic target and biomarker, and discusses natural product agents that inhibit SIX1-associated pro-oncogenic pathways.

LanguageEnglish

CategoryResearch & Report

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Pages20

Reading Time50 min

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Abstract

Introduction

Heliyon 10 (2024) e33204 Contents lists available at ScienceDirect Heliyon journal [homepage:](homepage: www.cell.com/heliyon)[ www.cell.com/heliyon](homepage: www.cell.com/heliyon) | Review article
Targeting sine oculis homeoprotein 1 (SIX1): A review of oncogenic roles and potential natural product therapeutics
Zhiwei Biana, 1 , Menny M. Benjamin b, 1 , Lucas Bialousowb , Yintai Tian a , G. Aaron Hobbs d, e , Dev Karanc , Yeun-Mun Choof, * , Mark T. Hamannb, ** , Xiaojuan Wang a, ***
a School of Pharmacy, Lanzhou University, Lanzhou, 730000, Gansu, China
b Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC, USAc Department of Pathology, Medical College of Wisconsin, Milwaukee, WI, USA
d Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA
e Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, USAf Chemistry Department, Faculty of Science, University of Malaya, 50603, Kuala Lumpur, Malaysia | | | | --- | --- | --- | | A R T I C L E I N F O | | A B S T R A C T | | Keywords:
Sine oculis homeoprotein 1 (SIX1)
Natural products Metastasis And metabolism | | Sine oculis homeoprotein 1 (SIX1), a prominent representative of the homeodomain transcription factors within the SIX family, has attracted significant interest owing to its role in tumorigenesis, cancer progression, and prognostic assessments. Initially recognized for its pivotal role in embryonic development, SIX1 has emerged as a resurgent factor across a diverse set of mammalian cancers. Over the past two decades, numerous investigations have emphasized SIX1’s dual significance as a developmental regulator and central player in oncogenic processes. A mounting body of evidence links SIX1 to the initiation of diverse cancers, encompassing enhanced cellular metabolism and advancement. This review provides an overview of the multifaceted roles of SIX1 in both normal development and oncogenic processes, emphasizing its importance as a possible therapeutic target and prognostic marker. Additionally, this review discusses the natural product agents that inhibit various pro-oncogenic mechanisms associated with SIX1. | 1. Introduction SIX1 is a member of the mammalian Six family of homeobox genes, which are homologous to the sine oculis (so) gene in Drosophila. These genes produce transcription factors that play crucial roles in the proliferation and survival of progenitor cells during the process of organ development [1]. Initially discovered in Drosophila as essential regulators of eye formation, SIX1 proteins are known to play a role in the expansion and differentiation of cell populations in various organs, such as the retina, craniofacial structures, auditory system, brain, lungs, muscles, kidneys, and gonads, among others [2–9]. * Corresponding author. ** Corresponding author. *** Corresponding author. E-mail addresses: [ymchoo@um.edu.my](ymchoo@um.edu.my) (Y.-M. Choo), [hamannm@musc.edu](hamannm@musc.edu) (M.T. Hamann), [Xiaojuan170@outlook.com](Xiaojuan170@outlook.com) (X. Wang). 1 These two authors contributed equally to this work. [https://doi.org/10.1016/j.heliyon.2024.e33204](https://doi.org/10.1016/j.heliyon.2024.e33204) Received 19 December 2023; Received in revised form 16 June 2024; Accepted 17 June 2024 Available online 17 June 2024 2405-8440/© 2024 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC license ([http://creativecommons.org/licenses/by-nc/4.0/](http://creativecommons.org/licenses/by-nc/4.0/)). SIX genes are broadly expressed throughout vertebrate embryogenesis, indicating their involvement in a variety of differentiation processes. A notable homeobox gene is the SIX1 homeoprotein, which plays a crucial role in the proliferation of progenitor cell populations during early embryogenesis and is essential for the de

FAQs

What is SIX1 and why is it important in cancer?

SIX1 is a homeodomain transcription factor in the SIX family. It is associated with tumorigenesis and cancer progression and is also relevant for prognostic assessments.

What roles does SIX1 play in normal development?

SIX1 is involved in organ development by regulating proliferation and survival of progenitor cell populations during embryogenesis. It is also necessary for development of multiple organs and tissues.

How does this review connect SIX1 with natural product therapeutics?

The review summarizes oncogenic mechanisms driven by SIX1 and discusses natural product agents that inhibit pro-oncogenic processes associated with SIX1.

Sep 21, 2026

Uploaded by Noah