The HMGA1 protoncogene frequently deregulated in cancer is a transcriptional target of E2F1

Abstract

Reactivation of the HMGA1 protoncogene is very frequent in human cancer, but still very little is known on the molecular mechanisms leading to this event. Prompted by the finding of putative E2F binding sites in the human HMGA1 promoter and by the frequent deregulation of the RB/E2F1 pathway in human carcinogenesis, we investigated whether E2F1 might contribute to the regulation of HMGA1 gene expression. Here we report that E2F1 induces HMGA1 by interacting with a 193 bp region of the HMGA1 promoter containing an E2F binding site surrounded by three putative Sp1 binding sites. Both gain and loss of function experiments indicate that Sp1 functionally interacts with E2F1 to promote HMGA1 expression. However, while Sp1 constitutively binds HMGA1 promoter, it is the balance between different E2F family members that tunes the levels of HMGA1 expression between quiescence and proliferation. Finally, we found increased HMGA1 expression in pituitary and thyroid tumors developed in Rb(+/-) mice, supporting the hypothesis that E2F1 is a novel important regulator of HMGA1 expression and that deregulation of the RB/E2F1 path might significantly contribute to HMGA1 deregulation in cancer.

HMGA Genes and Proteins in Development and Evolution

“…HMGA1 may be relevant in this context, as its overexpression is able to withdraw cells from this G0 arrest, suggesting that downregulation of HMGA1 is mechanistically essential for G0 arrest [168]. It was also shown that HMGA1 itself is a target of E2F1 [169].…”

“…, and E2F1 are able to bind to the HMGA1 promoter and regulate its expression [75,[166][167][168]. For example, the HMGA1 promoter contains an E2F binding site and three putative SP1 binding sites; in T98G glioblastoma cells, E2F1 binds to the HMGA1 promoter and cooperates with SP1 to regulate HMGA1 transcription [169]. Moreover, HMGA1 promotes E2F1 activity by displacing the histone deacetylase (HDAC) 1 from the pocket domain of pRB in the pRB/E2F1 complex.…”

Most of the tight positional conservation of transcription factor binding sites near the transcription start site reflects their co-localization within regulatory modules

“…Experiments supported E2F-Sp1 interactions near: dihydrofolate reductase in Chinese hamster [59], dihydrofolate reductase in human osteosarcoma [60], fibroblast CTP:phosphocholine cytidylyltransferase in mouse embryo [61], thymidine kinase in mouse [62], RIP140 in human [63], CDKN2A [64], HMGA1 [65], MYCN [66], and CDKN2C [67]. They also supported ETS-Sp1 interactions near the Runx2 P1 promoter [68], PAI-1 [69], ITGA11 [70], and Npr1 [71].…”

Thin Capitalisation Rules: A Second-Best Solution to the Cross-Border Debt Bias?

“…Chen et al, 210 Keen and King, 211 Klemm 212 and Massimi and Petroni 213 have provided comprehensive evaluations of these ACEvariants in practice, concluding that ACE-variants were quite successful in practice and did not have significant negative effects on corporate tax revenues. 214 Importantly, these leading commentators also observe that, of the ACE-variants no longer in operation, their abolition was attributable to political aspirations and the willingness of governments to introduce lower overall corporate tax rates, rather than to any fundamental design flaws in the ACE-variant system.…”