Tricho-rhino-phalangeal syndrome 1 protein functions as a scaffold required for ubiquitin-specific protease 4-directed histone deacetylase 2 de-ubiquitination and tumor growth

Abstract

BackgroundAlthough numerous studies have reported that tricho-rhino-phalangeal syndrome type I (TRPS1) protein, the only reported atypical GATA transcription factor, is overexpressed in various carcinomas, the underlying mechanism(s) by which it contributes to cancer remain unknown.MethodsBoth overexpression and knockdown of TRPS1 assays were performed to examine the effect of TRPS1 on histone deacetylase 2 (HDAC2) protein level and luminal breast cancer cell proliferation. Also, RT-qRCR, luciferase reporter assay and RNA-sequencing were used for transcription detection. Chromatin immunoprecipitation (ChIP) using H4K16ac antibody in conjunction with qPCR was used for determining H4K16ac levels in targeted genes. Furthermore, in vitro cell proliferation assay and in vivo tumor xenografts were used to detect the effect of TRPS1 on tumor growth.ResultsWe found that TRPS1 scaffolding recruits and enhances interaction between USP4 and HDAC2 leading to HDAC2 de-ubiquitination and H4K16 deacetylation. We detected repression of a set of cellular growth-related genes by the TRPS1-USP4-HDAC2 axis indicating it is essential in tumor growth. In vitro and in vivo experiments confirmed that silencing TRPS1 reduced tumor growth, whereas overexpression of HDAC2 restored tumor growth.ConclusionOur study deciphered the TRPS1-USP4-HDAC2 axis as a novel mechanism that contributes to tumor growth. Significantly, our results revealed the scaffolding function of TPRS1 in USP4-directed HDAC2 de-ubiquitination and provided new mechanistic insights into the crosstalk between TRPS1, ubiquitin, and histone modification systems leading to tumor growth.Electronic supplementary materialThe online version of this article (10.1186/s13058-018-1018-7) contains supplementary material, which is available to authorized users.

TRPS1 acts as a context-dependent regulator of mammary epithelial cell growth/differentiation and breast cancer development

“…Activity of the NuRD complex is involved in gene regulation of numerous processes including pluripotency during embryonic development or transcriptional events involved in cancer formation or progression (Basta and Rauchman 2015). TRPS1 stabilizes HDAC2 expression, and reduced cell viability caused by low TRPS1 levels can be rescued by HDAC2 overexpression (Wang et al 2018b), even though we did not observe any changes in HDAC1 or HDAC2 expression upon TRPS1 loss. In addition, we now show that DNA binding of the core enzymatic components of the NuRD complex (HDAC1 and HDAC2) is reduced upon TRPS1 loss.…”

“…TRPS1 is also shown to be essential and required for growth of (mostly hormone receptor-positive) breast cancers (Witwicki et al 2018). Indeed, several breast cancer cell lines show reduced growth both in vitro and in vivo upon loss of TRPS1 expression (Elster et al 2018;Wang et al 2018b;Witwicki et al 2018). In other settings, loss of TRPS1 expression appears to be promoting mammary tumor growth.…”

“…Trps1 was identified as a potential tumor suppressor gene in an insertional mutagenesis screen in a triple-negative breast cancer (TNBC) mouse model and reduced expression of TRPS1 was reported to increase in vivo growth of multiple TNBC cell lines (Rangel et al 2016). However, for other breast cancer cell lines in vivo cell growth is reported to decrease upon reduced TRPS1 expression (Elster et al 2018;Wang et al 2018b;Witwicki et al 2018). In vitro, TRPS1 was reported to be involved in regulation and restriction of ERα DNA binding and histone acetylation at enhancers (Serandour et al 2018) and required for maintenance of epithelial differentiation by suppression of ZEB2 (Stinson et al 2011;Huang et al 2016).…”

Transcriptional repressor GATA binding 1–mediated repression of SRY-box 2 expression suppresses cancer stem cell functions and tumor initiation

“…In this respect, we recently reported that TRPS1 promoted tumor growth by functioning as a scaffold to regulate USP4-directed HDAC2 deubiquitination. These observations provided a mechanistic insight into the tumor growth-promoting role of TRPS1 (35).…”

A PAK5–DNPEP–USP4 axis dictates breast cancer growth and metastasis

“…Another study indicated that USP4 promotes breast cancer cell invasion through the Relaxin/TGF‐β1/Smad2/MMP‐9 axis . Furthermore, a TRPS1–USP4–HDAC2 axis that contributes to tumor growth was established …”