Zhx2, or Zinc fingers and homeoboxes 2, is a transcriptional factor. It serves as a negative regulator of alpha fetal protein (AFP) and is involved in multiple cellular processes like cell proliferation, differentiation, lipid metabolism, and immunoregulation [1].

In various disease models, Zhx2 shows distinct roles. In clear cell renal cell carcinoma (ccRCC), VHL loss-of-function mutations lead to increased ZHX2 abundance and nuclear localization, and ZHX2 depletion inhibits VHL-deficient ccRCC cell growth in vitro and in vivo, suggesting it as an oncogene [4]. In triple-negative breast cancer (TNBC), ZHX2 amplification or overexpression promotes HIF1α oncogenic signaling, and its depletion inhibits cell growth, invasion, orthotopic tumor growth, and lung metastasis [5]. In contrast, in thyroid cancer, ZHX2 acts as a tumor suppressor. Its decreased expression in cancer tissues correlates with poor prognosis, and it inhibits metastasis by transcriptionally inhibiting S100A14 [6]. In acute liver injury, loss of Zhx2 promotes liver recovery by increasing mitochondrial OXPHOS in mouse models with partial hepatectomy or CCl4-induced liver injury [2]. In macrophage-related processes, myeloid-specific deletion of Zhx2 in mice affects macrophage polarization and the anti-tumor response, and also confers resistance to sepsis [3,8]. In pancreatic β-cells, β-cell-specific knockout of Zhx2 in mice leads to decreased β-cell proliferation and glucose intolerance, indicating its role in maintaining β-cell mass and function by regulating Pax6 [7].

In summary, Zhx2 has diverse functions in different biological processes and disease conditions. Gene knockout and conditional knockout mouse models have been crucial in revealing its role in diseases such as ccRCC, TNBC, thyroid cancer, acute liver injury, macrophage-related disorders, and diabetes, providing insights into potential therapeutic targets.

References:

1. Li, Na, Wu, Zhuanchang, Ma, Chunhong. 2022. ZHX2 in health and disease. In Frontiers in oncology, 12, 1038890. doi:10.3389/fonc.2022.1038890. https://pubmed.ncbi.nlm.nih.gov/36465389/

2. Zhang, Yankun, Fan, Yuchen, Hu, Huili, Yue, Xuetian, Ma, Chunhong. 2023. ZHX2 emerges as a negative regulator of mitochondrial oxidative phosphorylation during acute liver injury. In Nature communications, 14, 7527. doi:10.1038/s41467-023-43439-0. https://pubmed.ncbi.nlm.nih.gov/37980429/

3. Tan, Siyu, Wang, Zehua, Li, Na, Liang, Xiaohong, Ma, Chunhong. 2023. Transcription factor Zhx2 is a checkpoint that programs macrophage polarization and antitumor response. In Cell death and differentiation, 30, 2104-2119. doi:10.1038/s41418-023-01202-4. https://pubmed.ncbi.nlm.nih.gov/37582865/

4. Zhang, Jing, Wu, Tao, Simon, Jeremy, Baldwin, Albert S, Zhang, Qing. . VHL substrate transcription factor ZHX2 as an oncogenic driver in clear cell renal cell carcinoma. In Science (New York, N.Y.), 361, 290-295. doi:10.1126/science.aap8411. https://pubmed.ncbi.nlm.nih.gov/30026228/

5. Fang, Wentong, Liao, Chengheng, Shi, Rachel, Yang, Lee-Wei, Zhang, Qing. 2021. ZHX2 promotes HIF1α oncogenic signaling in triple-negative breast cancer. In eLife, 10, . doi:10.7554/eLife.70412. https://pubmed.ncbi.nlm.nih.gov/34779768/

6. Zhang, Yankun, Sun, Min, Gao, Lifen, Lu, Jinghui, Yue, Xuetian. 2022. ZHX2 inhibits thyroid cancer metastasis through transcriptional inhibition of S100A14. In Cancer cell international, 22, 76. doi:10.1186/s12935-022-02499-w. https://pubmed.ncbi.nlm.nih.gov/35151335/

7. Ding, Lu, Zhang, Yankun, Wang, Yingchun, Ma, Chunhong, Gao, Lifen. 2023. Zhx2 maintains islet β-cell mass and function by transcriptionally regulating Pax6. In iScience, 26, 106871. doi:10.1016/j.isci.2023.106871. https://pubmed.ncbi.nlm.nih.gov/37275527/

8. Wang, Zehua, Kong, Liang, Tan, Siyu, Liang, Xiaohong, Ma, Chunhong. 2020. Zhx2 Accelerates Sepsis by Promoting Macrophage Glycolysis via Pfkfb3. In Journal of immunology (Baltimore, Md. : 1950), 204, 2232-2241. doi:10.4049/jimmunol.1901246. https://pubmed.ncbi.nlm.nih.gov/32179636/