Transcriptional regulator which can act as an activator or a repressor. Inhibits the enhancer element of the AFP gene by binding to its AT-rich core sequence. In concert with SMAD-dependent TGF-beta signaling can repress the transcription of AFP via its interaction with SMAD2/3 (PubMed:25105025). Regulates the circadian locomotor rhythms via transcriptional activation of neuropeptidergic genes which are essential for intercellular synchrony and rhythm amplitude in the suprachiasmatic nucleus (SCN) of the brain (By similarity). Regulator of myoblasts differentiation through the binding to the AT-rich sequence of MYF6 promoter and promoter repression (PubMed:11312261). Down-regulates the MUC5AC promoter in gastric cancer (PubMed:17330845). In association with RUNX3, up-regulates CDKN1A promoter activity following TGF-beta stimulation (PubMed:20599712). Inhibits estrogen receptor (ESR1) function by selectively competing with coactivator NCOA3 for binding to ESR1 in ESR1-positive breast cancer cells (PubMed:20720010). Interacts with FNBP3 (By similarity). Interacts with ALKBH4 and PIAS3. Interacts with ESR1. Interacts with RUNX3. Interacts with TRIM25. Interacts with SMAD2 and SMAD3. Translocates from the cytoplasm to the nucleus following TGF-beta stimulation. Expressed in nuclear body (NB)-like dots in the nucleus some of which overlap or closely associate with PML body. Not found in normal gastric mucosa but found in gastric carcinoma cells (at protein level). Expression is higher in ER-positive breast tumors than ER-negative breast tumors (at protein level). Phosphorylation decreases its sensitivity to calpain-mediated proteolysis. Adult brain-derived ZFHX3 is sensitive, but embryonic brain-derived ZFHX3 is resistant to calpain 1-mediated proteolysis. Ubiquitinated, leading to its proteasomal degradation. Nuclear localization is essential for its sumoylation. Genetic variations in ZFHX3 are associated with atrial fibrillation and ischemic stroke in individuals of European ancestry. The sequence differs from that shown due translation of the 5'-UTR region.