Transcriptional factor HBP1 targets P16INK4A, upregulating its expression and consequently is involved in Ras-induced premature senescence

Abstract

Oncogene-mediated premature senescence has emerged as a potential tumor-suppressive mechanism in early cancer transitions. Many studies showed that Ras and p38 mitogen-activated protein kinase (MAPK) participate in premature senescence. Our previous work indicated that the HMG box-containing protein 1 (HBP1) transcription factor is involved in Ras-and p38 MAPK-induced premature senescence, but the mechanism of which has not yet been identified. Here, we showed that the p16 INK4A cyclin-dependent kinase inhibitor is a novel target of HBP1 participating in Ras-induced premature senescence. The promoter of the p16 INK4A gene contains an HBP1-binding site at position À426 to À433 bp from the transcriptional start site. HBP1 regulates the expression of the endogenous p16 INK4A gene through direct sequence-specific binding. With HBP1 expression and the subsequent increase of p16 INK4A gene expression, Ras induces premature senescence in primary cells. The data suggest a model in which Ras and p38 MAPK signaling engage HBP1 and p16 INK4A to trigger premature senescence. In addition, we report that HBP1 knockdown is also required for Ras-induced transformation. All the data indicate that the mechanism of HBP1-mediated transcriptional regulation is important for not only premature senescence but also tumorigenesis.

HBP1-Mediated Transcriptional Regulation of DNA Methyltransferase 1 and Its Impact on Cell Senescence

“…Confoundingly, we and others have reported that HBP1 can transcriptionally activate genes such as those for p16, p21 (29), MPO (30,31), and histone H1 (32), but the mechanism was unclear. Our previous work shows that protein acetylation is critical for p16 regulation (33,34), consistent with many reports of acetylation on other factors (e.g., MTA1, p63, CtBP, and NuRD [35][36][37]). Given its regulation of important cell cycle regulators, it is not surprising that overexpression of HBP1 induces cell cycle arrest and premature senescence in numerous cells and in organs (16,21,38,39).…”

“…We previously reported that HBP1 induces premature senescence through transcriptional activation of the p16 gene (33,34). We next asked if varying DNMT1 levels and DNA methylation might influence the interaction of HBP1 with the p16 promoter.…”

“…Soft-agar growth and tumorigenesis assay were conducted essentially as described previously (33). About 500,000 cells were implanted subcutaneously in NOD-SCID mice, which were then monitored for 6 weeks for tumor growth.…”

“…Given its regulation of important cell cycle regulators, it is not surprising that overexpression of HBP1 induces cell cycle arrest and premature senescence in numerous cells and in organs (16,21,38,39). For example, HBP1 participates in Ras-induced premature senescence through upregulation of p16 expression (33). Finally, other studies have implicated HBP1 in breast cancer progression that is associated with a poor prognosis (40), including as a target of a microRNA (miRNA) implicated in invasive breast cancer (41).…”

The protective effect of p16INK4a in oral cavity carcinomas: p16Ink4A dampens tumor invasion—integrated analysis of expression and kinomics pathways

“…[23][24][25] This supports the idea that different pathways of carcinogenesis affect treatment response and outcomes. The high 26,27 A large body of published data in the context of oropharyngeal and supraglottic squamous cell carcinoma confirm that p16 INK4a overexpression predicts increased radiosensitivity and improved survival. [11][12][13][14][15][16][17][18] Published data specific to oral cavity squamous cell carcinoma examining p16 INK4a , HPV status, and outcome are more limited.…”