Interaction and Collaboration of SP1, HIF-1, and MYC in Regulating the Expression of Cancer-Related Genes to Further Enhance Anticancer Drug Development

Abstract

Specificity protein 1 (SP1), hypoxia-inducible factor 1 (HIF-1), and MYC are important transcription factors (TFs). SP1, a constitutively expressed housekeeping gene, regulates diverse yet distinct biological activities; MYC is a master regulator of all key cellular activities including cell metabolism and proliferation; and HIF-1, whose protein level is rapidly increased when the local tissue oxygen concentration decreases, functions as a mediator of hypoxic signals. Systems analyses of the regulatory networks in cancer have shown that SP1, HIF-1, and MYC belong to a group of TFs that function as master regulators of cancer. Therefore, the contributions of these TFs are crucial to the development of cancer. SP1, HIF-1, and MYC are often overexpressed in tumors, which indicates the importance of their roles in the development of cancer. Thus, proper manipulation of SP1, HIF-1, and MYC by appropriate agents could have a strong negative impact on cancer development. Under these circumstances, these TFs have naturally become major targets for anticancer drug development. Accordingly, there are currently many SP1 or HIF-1 inhibitors available; however, designing efficient MYC inhibitors has been extremely difficult. Studies have shown that SP1, HIF-1, and MYC modulate the expression of each other and collaborate to regulate the expression of numerous genes. In this review, we provide an overview of the interactions and collaborations of SP1, HIF1A, and MYC in the regulation of various cancer-related genes, and their potential implications in the development of anticancer therapy.

Keywords: MYC; SP1; cancer; hypoxia-inducible factor 1.

Figure 1

The promoter structures of human SP1, HIF1A, and MYC genes. The consensus sequences and their potential binding proteins are shown in each promoter. SP1 binds to SP1 consensus sequences (GC box) as well as NF-Y and E2F consensus sequences. HIF-1 binds to the HRE. MYC, similarly to SP1, binds to E2F. Myc-associated zinc finger protein (MAZ) is an important regulatory protein associated with MYC gene expression and binds to MAZ consensus sequences [90,92]. The nucleotide numbers are numbered from the transcription start site (TSS). The TSS for MYC gene promoter is for the P1 promoter [90,92].

Figure 2

Schematic of the mechanism of activation of SP1 by HIF1A and that of HIF1A by SP1. (A) The mechanism of SP1 activation by HIF1A. (B–D) The mechanism of HIF1A activation by SP1. While HIF1A regulates SP1 expression via binding to the promoter of a SP1 gene, SP1 can regulate HIF1A expression at both the mRNA level (B,C) and protein level (D). PKC: protein kinase C.

Figure 3

Locations of SP1 and HIF-1 consensus sequences in the promoters of genes which are involved in the regulation of CSCs. Schematic of the locations of SP1 and HIF-1 consensus sequences in the promoters of human TERT, BMI1, CD147, and CD133 genes, which are all involved in the regulation of CSCs. The nucleotide numbers are numbered from the ATG (translation initiation) sites. HIF-1 binds to the ETS consensus sequence in the CD133 promoter, whereas HIF-1 binds to the HRE in other promoters. The nucleotide sequences of the HRE are similar to those of the E-Box, which is a consensus sequence for MYC binding. The objects with descriptions of ‘MYC’ or ‘HIF’ in the circles indicate the TFs. The MYC TF, designated by the ‘MYC’ in the circle, binds to the E-Box or the MYC consensus sequences in the vicinity of CpG islands (SP1 consensus sequences), whereas the HIF-1 TF, designated by the ‘HIF’ in the circle, binds to the HRE or the ETS.

Figure 4

Scheme to illustrate what could happen when cancers are treated with a combination of HIF-1 and SP1 inhibitors. There are intricate mechanisms underlying the collaboration of HIF-1 and SP1 to regulate cancer-related cellular mechanisms. HIF-1 and SP1 usually induce the expression of each other (as described in Section 3) and activate their target genes in corporation (as described in Section 4). Therefore, it is expected that combination treatment of HIF and SP1 inhibitors can specifically suppress the activity of cancer-related cellular mechanisms.