SOX2 and p63 colocalize at genetic loci in squamous cell carcinomas
Hideo Watanabe, … , Matthew Meyerson, Adam J. Bass
Hideo Watanabe, … , Matthew Meyerson, Adam J. Bass
Published March 3, 2014
Citation Information: J Clin Invest. 2014;124(4):1636-1645. https://doi.org/10.1172/JCI71545.
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SOX2 and p63 colocalize at genetic loci in squamous cell carcinomas

Abstract

The transcription factor SOX2 is an essential regulator of pluripotent stem cells and promotes development and maintenance of squamous epithelia. We previously reported that SOX2 is an oncogene and subject to highly recurrent genomic amplification in squamous cell carcinomas (SCCs). Here, we have further characterized the function of SOX2 in SCC. Using ChIP-seq analysis, we compared SOX2-regulated gene profiles in multiple SCC cell lines to ES cell profiles and determined that SOX2 binds to distinct genomic loci in SCCs. In SCCs, SOX2 preferentially interacts with the transcription factor p63, as opposed to the transcription factor OCT4, which is the preferred SOX2 binding partner in ES cells. SOX2 and p63 exhibited overlapping genomic occupancy at a large number of loci in SCCs; however, coordinate binding of SOX2 and p63 was absent in ES cells. We further demonstrated that SOX2 and p63 jointly regulate gene expression, including the oncogene ETV4, which was essential for SOX2-amplified SCC cell survival. Together, these findings demonstrate that the action of SOX2 in SCC differs substantially from its role in pluripotency. The identification of the SCC-associated interaction between SOX2 and p63 will enable deeper characterization the downstream targets of this interaction in SCC and normal squamous epithelial physiology.

Authors

Hideo Watanabe, Qiuping Ma, Shouyong Peng, Guillaume Adelmant, Danielle Swain, Wenyu Song, Cameron Fox, Joshua M. Francis, Chandra Sekhar Pedamallu, David S. DeLuca, Angela N. Brooks, Su Wang, Jianwen Que, Anil K. Rustgi, Kwok-kin Wong, Keith L. Ligon, X. Shirley Liu, Jarrod A. Marto, Matthew Meyerson, Adam J. Bass

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Figure 6

Identification of target genes coregulated by SOX2 and p63.

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Identification of target genes coregulated by SOX2 and p63. (A) Gene exp...
(A) Gene expression changes by suppression of SOX2 and of TP63 in KYSE70 cells. Cloud color represents plot density. Changes were significantly positively correlated (trend line; r = 0.492). (B) Overlap among genes with high-confidence SOX2-p63–co-occupied loci within 50 kb from their TSS, and genes whose expression was downregulated (>1.5 fold) after suppression of SOX2 or TP63, in KYSE70 cells. See Supplemental Table 5 for the 93 genes at the intersection. (C) Correlation of expression of the 93 genes co-occupied by SOX2 and p63 and downregulated upon SOX2 and TP63 suppression with SOX2 mRNA expression from the lung SCC TCGA. Of these 93 genes within TCGA lung SCC samples with the top quartile of SOX2 expression, 5 genes were on the list of Cancer Gene Census (green circles). (D) ETV4 mRNA, determined by quantitative RT-PCR, before and after induction of shSOX2 or shTP63 in KYSE70 cells (the stable cell lines used in Figure 4). Mean ratio ± SD of triplicates is shown. *P < 0.05, 2-way ANOVA with Bonferroni post-test.