ZFHX3 is indispensable for ERβ to inhibit cell proliferation via MYC downregulation in prostate cancer cells

作者：Qingxia Hu, Baotong Zhang, Rui Chen, Changying Fu, Jun Arita, Xing Fu, Juan Li, Liya Fu, Zhiqian Zhang, Jin‐Tang Dong · 发表于：Oncogenesis · 年份：2019 · DOI：10.1038/s41389-019-0138-y · 被引用次数：57 · 研究领域：Cancer-related gene regulation、Estrogen and related hormone effects、Prostate Cancer Treatment and Research

Both estrogen receptor 2 (ESR2, also known as estrogen receptor beta (ERβ)) and the zinc-finger homeobox 3 (ZFHX3, also known as ATBF1 for AT motif-binding factor 1) modulate prostate development and suppress prostatic tumorigenesis in mice. ZFHX3 is integral to proper functions of ESR1 (i.e., estrogen receptor alpha (ERα)), which belongs to the same family of proteins as ESR2, but is hardly expressed in prostate epithelial cells. It is not clear how ZFHX3 suppresses prostatic tumorigenesis. In this study, we investigated whether ZFHX3 and ERβ functionally interact with each other in the suppression of prostatic tumorigenesis. In two androgen receptor (AR)-positive prostate cancer cell lines, C4-2B and LNCaP, we first validated ERβ's tumor suppressor activity indicated by the inhibition of cell proliferation and repression of MYC expression. We found that loss of ZFHX3 increased cell proliferation and MYC expression, and downregulation of MYC was necessary for ZFHX3 to inhibit cell proliferation in the same cell lines. Importantly, loss of ZFHX3 prevented ERβ from suppressing cell proliferation and repressing MYC transcription. Biochemically, ERβ and ZFHX3 physically interacted with each other and they both occupied the same region of the common MYC promoter, even though ZFHX3 also bound to another region of the MYC promoter. Higher levels of ZFHX3 and ERβ in human prostate cancer tissue samples correlated with better patient survival. These findings establish MYC repression ...