Specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4 are non-oncogene addiction genes in cancer cells.

Erik Hedrick,Stephen Safe,Kyounghyun Kim,Yating Cheng,Un-Ho Jin

doi:10.18632/oncotarget.7925

Erik Hedrick, Stephen Safe + Show 3 more

Open Access

https://doi.org/10.18632/oncotarget.7925

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Journal: Oncotarget	Publication Date: Mar 5, 2016
Citations: 86	License type: CC BY 2.5

Affiliation: Texas A&M University, University of Cincinnati

Abstract

Specificity protein (Sp) transcription factor (TF) Sp1 is overexpressed in multiple tumors and is a negative prognostic factor for patient survival. Sp1 and also Sp3 and Sp4 are highly expressed in cancer cells and in this study, we have used results of RNA interference (RNAi) to show that the three TFs individually play a role in the growth, survival and migration/invasion of breast, kidney, pancreatic, lung and colon cancer cell lines. Moreover, tumor growth in athymic nude mice bearing L3.6pL pancreatic cancer cells as xenografts were significantly decreased in cells depleted for Sp1, Sp3 and Sp4 (combined) or Sp1 alone. Ingenuity Pathway Analysis (IPA) of changes in gene expression in Panc1 pancreatic cancer cells after individual knockdown of Sp1, Sp3 and Sp4 demonstrates that these TFs regulate genes and pathways that correlated with the functional responses observed after knockdown but also some genes and pathways that inversely correlated with the functional responses. However, causal IPA analysis which integrates all pathway-dependent changes in all genes strongly predicted that Sp1-, Sp3- and Sp4-regulated genes were associated with the pro-oncogenic activity. These functional and genomic results coupled with overexpression of Sp transcription factors in tumor vs. non-tumor tissues and decreased Sp1 expression with age indicate that Sp1, Sp3 and Sp4 are non-oncogene addiction (NOA) genes and are attractive drug targets for individual and combined cancer chemotherapies.

Highlights

Specificity protein (Sp) transcription factors (TFs) Sp1, Sp3 and Sp4 are members of the Sp/Krüppel-like family (KLF), and results from Sp knockout mouse models demonstrate the importance of Sp genes to embryonic growth and early development [reviewed in 1]
Most previous functional studies have focused on Sp1; results illustrated in Figure 1 clearly demonstrate that both Sp3 and Sp4 significantly contribute to the growth, survival and migration/invasion of the eight cancer cells lines and comparable effects were observed after individual knockdown of these transcription factors
In a parallel experiment, combined knockdown of Sp1, Sp3 and Sp4 or individual knockdown of Sp1 in L3.6pL cells used in an athymic nude mouse xenograft model showed that loss of Sp TFs resulted in a significant inhibition of tumor growth and tumor weights (Figure 1D and 1E)

Summary

Introduction

Specificity protein (Sp) transcription factors (TFs) Sp1, Sp3 and Sp4 are members of the Sp/Krüppel-like family (KLF), and results from Sp knockout mouse models demonstrate the importance of Sp genes to embryonic growth and early development [reviewed in 1]. Several studies report that high expression of Sp1 and, in some cases, Sp3 in tumor vs non-tumor tissue are negative prognostic factors for patients with pancreatic, glioma, colon, gastric, head and neck, prostate, lung and breast cancers [5,6,7,8,9,10,11,12,13]. Studies in cancer cell lines show that Sp1, Sp3 and Sp4 are highly expressed, and RNA interference (RNAi) studies indicate that Sp transcription factors regulate genes associated with cell proliferation, survival and migration/invasion [reviewed in 14]. Since Sp1 regulates expression of both pro-oncogenic and tumor suppressorlike genes, it has been suggested that “a more complete understanding of the function of Sp1 in cancer is required to validate its potential as a therapeutic target” [17]

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