GATA binding protein 1 recruits histone deacetylase 2 to the promoter region of nuclear receptor binding protein 2 to affect the tumor microenvironment and malignancy of thyroid carcinoma

Abstract

The tumor microenvironment (TME) and activated angiogenesis in thyroid carcinoma (TC) are critical for tumor growth and metastasis. Nuclear receptor binding protein 2 ( NRBP2 ) has been suggested as a tumor suppressor. This study examines the function of NRBP2 in the progression of TC and the regulatory mechanism. By analyzing bioinformatic tools including GSE165724 dataset and the Cancer Genome Atlas system, we predicted NRBP2 as a poorly expressed gene in TC. Decreased NRBP2 expression was detected in TC tumor tissues and cells. Poor expression of NRBP2 was linked to unfavorable prognosis of patients. GATA binding protein 1 ( GATA1 ) was found as a negative regulator of NRBP2 . It recruited histone deacetylase2 ( HDAC2 ) to the NRBP2 promoter to trigger histone deacetylation. NRBP2 overexpression suppressed growth of TC cells, and it reduced expression of TME markers, M2 polarization of macrophages, and angiogenesis in TC. Similar results were reproduced in vivo in nude mice. However, the anti-oncogenic roles of NRBP2 were blocked after further overexpression of GATA1 or HDAC2 . In summary, this study demonstrates that GATA1 recruits HDAC2 to the NRBP2 promoter and enhances the TME and angiogenesis in TC cells.

HDAC2 as a target for developing anti-cancer drugs

“…GATA family of TF1 GATA-binding protein 1 (GATA1) recruited HDAC2 to NRBP2 promoter sequences to suppress the expression of NRBP2 [27] . NRBP2 overexpression suppressed the growth of TC cells, M2 polarization of macrophages, and angiogenesis in TC [42] .…”

“…Decreased nuclear receptor-binding protein 2 (NRBP2) expression was observed in thyroid cancer (TC) tissues and cells [42] . Low levels of NRBP2 predicted the poor prognosis of patients with TCs [42] .…”

“…Decreased nuclear receptor-binding protein 2 (NRBP2) expression was observed in thyroid cancer (TC) tissues and cells [42] . Low levels of NRBP2 predicted the poor prognosis of patients with TCs [42] . GATA family of TF1 GATA-binding protein 1 (GATA1) recruited HDAC2 to NRBP2 promoter sequences to suppress the expression of NRBP2 [27] .…”

Histone acetylation modifications: A potential targets for the diagnosis and treatment of papillary thyroid cancer

“…The effect of the HDACs on the PTC is shown in Figure 3 . In fact, HDAC1 and HDAC2 expression levels are mildly increased in PTC tissues relative to normal tissues ( 37 ), Nuclear receptor binding protein 2 (NRBP2) reduces TC tumorigenesis and M2 macrophage infiltration in vivo , GATA binding protein 1 recruits HDAC2 to the NRBP2 promoter region, inhibits NRBP2 expression by reducing H3K9ac levels, blocks NRBP2 inhibition in PTC histiocytes and BCPAP and TPC-1 cell lines, and thereby promotes the formation of tumor microenvironment(TME) and activates angiogenesis ( 38 ). A META analysis showed that SIRT1 overexpression was detrimental to the overall survival of patients with solid malignancies ( 39 ), and SIRT1 nuclear staining was approximately 2.5-fold higher in PTC tissues than in normal tissues.…”