HOXB4 inhibits the proliferation and tumorigenesis of cervical cancer cells by downregulating the activity of Wnt/β-catenin signaling pathway

Abstract

Homeobox B4 (HOXB4), which belongs to the homeobox (HOX) family, possesses transcription factor activity and has a crucial role in stem cell self-renewal and tumorigenesis. However, its biological function and exact mechanism in cervical cancer remain unknown. Here, we found that HOXB4 was markedly downregulated in cervical cancer. We demonstrated that HOXB4 obviously suppressed cervical cancer cell proliferation and tumorigenic potential in nude mice. Additionally, HOXB4-induced cell cycle arrest at the transition from the G0/G1 phase to the S phase. Conversely, loss of HOXB4 promoted cervical cancer cell growth both in vitro and in vivo. Bioinformatics analyses and mechanistic studies revealed that HOXB4 inhibited the activity of the Wnt/β-catenin signaling pathway by direct transcriptional repression of β-catenin. Furthermore, β-catenin re-expression rescued HOXB4-induced cervical cancer cell defects. Taken together, these findings suggested that HOXB4 directly transcriptional repressed β-catenin and subsequently inactivated the Wnt/β-catenin signaling pathway, leading to significant inhibition of cervical cancer cell growth and tumor formation.

Overexpression of HOXB4 Promotes Protection of Bone Marrow Mesenchymal Stem Cells Against Lipopolysaccharide-Induced Acute Lung Injury Partially Through the Activation of Wnt/β-Catenin Signaling

“…However, previous research showed that HOXB4 directly acts on the Wnt/β-catenin pathway and exerts its anti-tumor effects by reducing Wnt/β-catenin activity. 60 …”

Homeobox Genes in Cancers: From Carcinogenesis to Recent Therapeutic Intervention

“…Therefore, considering the use of HOX protein as cancer therapeutic targets, its interaction with cofactors needs to be determined. Therapeutic values of HOX factors in human cancer are seen in Table 2 ( 4 , 7 , 13 , 14 , 17 , 18 , 22 , 23 , 25 – 27 , 29 , 31 , 32 , 35 , 41 , 45 , 56 , 57 , 68 , 71 , 72 , 81 , 82 , 84 , 87 , 88 , 90 , 97 , 116 , 117 , 127 , 128 , 132 – 135 , 137 , 141 , 147 , 148 , 153 , 166 , 167 ).…”

“…Regulation of HOX factors in various tumor types described in this figure legend. [brain cancer mainly includes the glioma and neuroblastoma (4-11), lung cancer(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24), hepatocellular carcinoma(25)(26)(27)(28)(29)(30)(31), bladder cancer(32,33), cholangiocarcinoma(34), head and neck squamous cell carcinoma(35,36), breast cancer(21-23, 37- 54), gastric carcinoma and esophagus cancer(55)(56)(57)(58)(59)(60)(61)(62)(63)(64), prostate cancer and renal carcinoma(43,(65)(66)(67)(68)(69)(70)(71)(72), ovarian cancer (73-79), endometrial cancer and cervical cancer(80)(81)(82)(83)(84), leukemia<...>…”

Epigenetic Regulation of the Wnt/β-Catenin Signaling Pathway in Cancer

“…In a recent study, it was shown to inhibit cancer cell proliferation and further tumorigenesis by inhibiting β-catenin at the transcriptional level by binding to its promoter in cervical cancer cells. Interestingly, several other Wnt related genes were found to be downregulated in cells overexpressing HOXB4, including MYC , whereas genes such as FZD8 , DKK1 , and AXIN2 were upregulated ( Lei et al, 2021 ).…”