ZBTB2 is Recruited to a Specific Subset of HIF-1 Target Loci to Facilitate Full Gene Expression Under Hypoxia.

The cellular response to hypoxia is mainly governed by a transcription factor, hypoxia-inducible factor 1 (HIF-1). Although upregulation of HIF-1 target genes has been hypothesized to require interaction of HIF-1 with other coactivators, much remains to be elucidated regarding the underlying mechanisms. Here, we demonstrate that zinc finger and BTB domain-containing protein 2 (ZBTB2) enhances the expression of certain HIF-1 target genes under hypoxia. ChIP-Seq analysis showed that there is a subset of HIF-1 target genes with overlapping HIF-1 and ZBTB2 peaks. Examination of a representative gene, EGFR antisense RNA 1 (EGFR-AS1), showed that HIF-1 binding to the consensus hypoxia-responsive element (HRE) sequence resulted in the recruitment of ZBTB2 to the gene locus and increased p300-mediated histone acetylation, leading to enhanced gene expression under hypoxia. In contrast, expression of HIF-1 target genes lacking ZBTB2 peaks, such as carbonic anhydrase 9 (CA9), was not upregulated by ZBTB2. These findings demonstrate that ZBTB2 is a novel factor that can be recruited to the vicinity of HREs on a subset of HIF-1 target gene loci, and is required for their full expression under hypoxia.

ZBTB2 links p53 deficiency to HIF-1-mediated hypoxia signaling to promote cancer aggressiveness.

Aberrant activation of the hypoxia-inducible transcription factor HIF-1 and dysfunction of the tumor suppressor p53 have been reported to induce malignant phenotypes and therapy resistance of cancers. However, their mechanistic and functional relationship remains largely unknown. Here, we reveal a mechanism by which p53 deficiency triggers the activation of HIF-1-dependent hypoxia signaling and identify zinc finger and BTB domain-containing protein 2 (ZBTB2) as an important mediator. ZBTB2 forms homodimers via its N-terminus region and increases the transactivation activity of HIF-1 only when functional p53 is absent. The ZBTB2 homodimer facilitates invasion, distant metastasis, and growth of p53-deficient, but not p53-proficient, cancers. The intratumoral expression levels of ZBTB2 are associated with poor prognosis in lung cancer patients. ZBTB2 N-terminus-mimetic polypeptides competitively inhibit ZBTB2 homodimerization and significantly suppress the ZBTB2-HIF-1 axis, leading to antitumor effects. Our data reveal an important link between aberrant activation of hypoxia signaling and loss of a tumor suppressor and provide a rationale for targeting a key mediator, ZBTB2, to suppress cancer aggressiveness.

An Overview of the Recent Development of Anticancer Agents Targeting the HIF-1 Transcription Factor.

Hypoxia, a characteristic feature of solid tumors, is associated with the malignant phenotype and therapy resistance of cancers. Hypoxia-inducible factor 1 (HIF-1), which is responsible for the metazoan adaptive response to hypoxia, has been recognized as a rational target for cancer therapy due to its critical functions in hypoxic regions. In order to efficiently inhibit its activity, extensive efforts have been made to elucidate the molecular mechanism underlying the activation of HIF-1. Here, we provide an overview of relevant research, particularly on a series of HIF-1 activators identified so far and the development of anticancer drugs targeting them.