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

Background: Although numerous studies have reported that tricho-rhino-phalangeal syndrome type 1 (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. Methods: Both 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. Results: We 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. Conclusion: Our 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.