Zinc Fingers and Homeobox Family in Cancer: A Double-Edged Sword

Abstract

The zinc fingers and homeobox (ZHX) family includes ZHX1, ZHX2, and ZHX3, and their proteins have similar unique structures, containing two C2H2-type zinc finger motifs and four or five HOX-like homeodomains. The members of the ZHX family can form homodimers or heterodimers with each other or with a subunit of nuclear factor Y. Previous studies have suggested that ZHXs can function as positive or negative transcriptional regulators. Recent studies have further revealed their biological functions and underlying mechanisms in cancers. This review summarized the advances of ZHX-mediated functions, including tumor-suppressive and oncogenic functions in cancer formation and progression, the molecular mechanisms, and regulatory functions, such as cancer cell proliferation, migration, invasion, and metastasis. Moreover, the differential expression levels and their association with good or poor outcomes in patients with various malignancies and differential responses to chemotherapy exert opposite functions of oncogene or tumor suppressors. Therefore, the ZHXs act as a double-edged sword in cancers.

Sunitinib Treatment of VHL C162F Cells Slows Down Proliferation and Healing Ability via Downregulation of ZHX2 and Confers a Mesenchymal Phenotype

“…We next focused on ZHX2, a protein of the zinc-fingers and homeoboxes (ZHX) family known to act as an oncogene in RCC in favor of proliferation and migration ( Figure 3 ) [ 12 , 13 , 15 ].…”

“…Several studies have indicated that ZHX2, a member of the ZHX (Zinc fingers and homeoboxes) family, has been involved in many types of cancer [ 12 ]. It has been reported that this transcription factor interferes with VHL regulation and evidence has been provided that shows it is associated with ccRCC initiation [ 13 , 14 ].…”

“…More importantly, Li et al identifies ZHX2 acting as an oncogenic driver in ccRCC where hypoxia-inducible factors (HIF1 and HIF2) are deregulated [ 16 ]. ZHX2 drives proliferation, migration, colony formation and invasion via activating multiple proteins including Twist, Snail, VEGF, MEK, ERK 1/2 [ 12 , 17 ]. Based on these findings, ZHX2 has been identified as a potential new therapeutic target for ccRCC patients [ 13 ].…”

ZHX2 alleviates vascular remodeling and smooth muscle cell proliferation by transcriptional regulation of GADD45G

“…More and more evidence shows that ZHX2 is an important regulator of various biological processes, including regulating the development of various cancers such as liver cancer, gastric cancer, and thyroid cancer, and participating in lipid metabolism, cell differentiation, and development, NK cell maturation, and macrophage cell polarization, etc (33). Many literatures have reported that ZHX2 has an inhibitory effect on the proliferation and migration of different types of cells (17,21,(34)(35)(36)(37)(38)(39). Some literature reported that ZHX2 may be related to apoptosis (35,37).…”

“…The zinc fingers and homeobox (ZHX) family includes ZHX1, ZHX2, and ZHX3, and these proteins have similar unique structures, containing two C2H2-type zinc finger motifs and four or five HOX-like homeodomains (17). Previous studies have suggested that ZHXs can function as positive (18) or negative transcriptional regulators (19).…”