SIX4 activates Akt and promotes tumor angiogenesis.

Abstract	Angiogenesis plays important roles in solid tumors progression. Growth factors such as vascular endothelial growth factors (VEGFs) can induce angiogenesis and hypoxia promotes the expression of VEGFs through activating hypoxia-inducible factor 1 (HIF-1α). However, the regulation of HIF-1α still not been fully understood. Here, we demonstrate that the Sine Oculis Homeobox Homolog 4 (SIX4) is up-regulated in colorectal cancer (CRC) and high expression of SIX4 predicts a poor prognosis. Overexpression of SIX4 enhances tumor growth and angiogenesis in vitro and in vivo, while knockdown of SIX4 inhibits tumor growth and angiogenesis. Furthermore, we show that SIX4 increases the expression of VEGF-A by coordinating with the HIF-1α. Mechanically, we explore that SIX4 up-regulates the expression of HIF-1α depending on Akt activation. Collectively, we demonstrate that SIX4 is functional in regulating tumor angiogenesis and SIX4 might be used as anti-angiogenic therapy in CRC.
Authors	Xuling Sun, Fuqing Hu, Zhenlin Hou, Qianzhi Chen, Jingqin Lan, Xuelai Luo, Guihua Wang, Junbo Hu, Zhixin Cao
Journal	Experimental cell research (Exp Cell Res) Vol. 383 Issue 1 Pg. 111495 (10 01 2019) ISSN: 1090-2422 [Electronic] United States
PMID	31301290 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright	Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
Chemical References	Biomarkers, Tumor Homeodomain Proteins SIX4 protein, human Trans-Activators AKT1 protein, human Proto-Oncogene Proteins c-akt
Topics	Animals Apoptosis Biomarkers, Tumor (genetics, metabolism) Cell Proliferation Colorectal Neoplasms (blood supply, metabolism, pathology) Female Gene Expression Regulation, Neoplastic Homeodomain Proteins (genetics, metabolism) Humans Lymphatic Metastasis Male Mice Mice, Inbred BALB C Mice, Nude Middle Aged Neovascularization, Pathologic (metabolism, pathology) Prognosis Proto-Oncogene Proteins c-akt (genetics, metabolism) Signal Transduction Survival Rate Trans-Activators (genetics, metabolism) Tumor Cells, Cultured Wound Healing Xenograft Model Antitumor Assays

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