Transcription factor HBP1 is a direct anti-cancer target of transcription factor FOXO1 in invasive oral cancer

Abstract

Either FOXO1 or HBP1 transcription factor is a downstream effector of the PI3K/Akt pathway and associated with tumorigenesis. However, the relationship between FOXO1 and HBP1 in oral cancer remains unclear. Analysis of 30 oral tumor specimens revealed that mean mRNA levels of both FOXO1 and HBP1 in non-invasive and invasive oral tumors were found to be significantly lower than that of the control tissues, and the status of low FOXO1 and HBP1 (< 0.3 fold of the control) was associated with invasiveness of oral tumors. To investigate if HBP1 is a direct transcription target of FOXO1, we searched potential FOXO1 binding sites in the HBP1 promoter using the MAPPER Search Engine, and two putative FOXO1 binding sites located in the HBP1 promoter –132 to –125 bp and –343 to –336 bp were predicted. These binding sites were then confirmed by both reporter gene assays and the in cellulo ChIP assay. In addition, Akt activity manipulated by PI3K inhibitor LY294002 or Akt mutants was shown to negatively affect FOXO1-mediated HBP1 promoter activation and gene expression. Last, the biological significance of the FOXO1-HBP1 axis in oral cancer malignancy was evaluated in cell growth, colony formation, and invasiveness. The results indicated that HBP1 knockdown potently promoted malignant phenotypes of oral cancer and the suppressive effect of FOXO1 on cell growth, colony formation, and invasion was alleviated upon HBP1 knockdown in invasive oral cancer cells. Taken together, our data provide evidence for HBP1 as a direct downstream target of FOXO1 in oral cancer malignancy.

Glioma exosomes mediate the expansion and function of myeloid‐derived suppressor cells through microRNA‐29a/Hbp1 and microRNA‐92a/Prkar1a pathways

“…We provide the first evidence showing that miR‐29a and miR‐92a promote the expansion of functional MDSCs via the Hbp1 /cell cycle pathway and the Prkar1a /PKA/p‐STAT3 pathway, respectively. HBP1 inhibits the G1 phase of the cell cycle and inhibits the proliferation of many types of tumor cells . However, few studies have investigated the relationship between MDSCs and cell cycle progression, and the effect of HBP1 on MDSCs has not been studied.…”

“…HBP1 inhibits the G1 phase of the cell cycle and inhibits the proliferation of many types of tumor cells. 31,32 However, few studies have investigated the relationship between MDSCs and cell cycle progression, and the effect of HBP1 on MDSCs has not been studied. In our study, the miR-29a-mediated silencing of Hbp1 induced cell cycle progression in MDSCs.…”

MiR‐21 improves invasion and migration of drug‐resistant lung adenocarcinoma cancer cell and transformation of EMT through targeting HBP1

“…In addition, a previous study of Chan et al. investigated the influence of HBP1 on invasive oral cancer . Suppression of HBP1 could also promote human breast cancer cell migration and invasion .…”

“…HBP1, a tumor suppressor, has been shown to contribute to cell senescence and block tumorigenesis in several cancers [42], including lung adenocarcinoma (H1299 [p53−/−], A549), hepatocellular carcinoma (HepG2), and osteogenic sarcoma (U2OS). In addition, a previous study of Chan et al investigated the influence of HBP1 on invasive oral cancer [43]. Suppression of HBP1 could also promote human breast cancer cell migration and invasion [44].…”

Deciphering the roles of FOXO1 in human neoplasms

“…Analysis of 30 noninvasive and invasive oral tumor specimens indicated that mean mRNA levels of both FOXO1 and HBP1 are significantly lower than those of control tissues, and a low FOXO1 and HBP1 status (<0.3‐fold of the control) is associated with enhanced invasiveness of oral tumors. Specifically, HBP1 knockdown potently downregulates FOXO1 and promotes the expression of malignant phenotypes, colony formation and invasion of oral cancer …”