Growing evidence indicates that ubiquitin ligases play a critical role in the hypoxia response. Among them, Siah2, a RING finger ligase, is an important regulator of pathways activated under hypoxia. Siah2 regulates prolyl hydroxylases PHD3 and 1 under oxygen concentration of 2% to 5%, thereby allowing accumulation of hypoxia-inducible factor (HIF)-1α, a master regulator of the hypoxia response within the range of physiological normoxic to mild hypoxic conditions. Growing evidence also indicates an important function for Siah2 in tumor development and progression based on pancreatic cancer, mammary tumor, and melanoma mouse models. This review summarizes our current understanding of Siah2 regulation and function with emphasis on hypoxia and tumorigenesis. (Mol Cancer Res 2009;7(4):443–51)

Eukaryotes are often subjected to different kinds of stress. In order to adjust to such circumstances, eukaryotes activate stress–response pathways and regulate gene expression. Eukaryotic gene expression consists of many different steps, including transcription, RNA processing, RNA transport, and translation. In this review article, we focus on both transcriptional and post-transcriptional regulations of gene expression under hypoxic conditions. In the first part of the review, transcriptional regulations mediated by various transcription factors including Hypoxia-Inducible Factors (HIFs) are described. In the second part, we present RNA splicing regulations under hypoxic conditions, which are mediated by splicing factors and their kinases. This work summarizes and discusses the emerging studies of those two gene expression machineries under hypoxic conditions.

Downregulation of pyruvate dehydrogenase (PDH) is critical for the aberrant preferential activation of glycolysis in cancer cells under normoxic conditions. Phosphorylation-dependent inhibition of PDH is a relevant event in this process, but it is not durable as it relies on PDH kinases that are activated ordinarily under hypoxic conditions. Thus, it remains unclear how PDH is durably downregulated in cancer cells that are not hypoxic. Building on evidence that PDH activity depends on the stability of a multi-protein PDH complex, we found that the PDH-E1β subunit of the PDH complex is downregulated to inhibit PDH activity under conditions of prolonged hypoxia. After restoration of normoxic conditions, reduced expression of PDH-E1β was sustained such that glycolysis remained highly activated. Notably, PDH-E1β silencing in cancer cells produced a metabolic state strongly resembling the Warburg effect, but inhibited tumor growth. Conversely, enforced exogenous expression of PDH-E1β durably increased PDH activity and promoted the malignant growth of breast cancer cells in vivo. Taken together, our results establish the specific mechanism through which PDH acts as an oncogenic factor by tuning glycolytic metabolism in cancer cells. Significance: This seminal study offers a mechanistic explanation for why glycolysis is aberrantly activated in normoxic cancer cells, offering insights into this long-standing hallmark of cancer termed the Warburg effect. Cancer Res; 78(7); 1592–603. ©2018 AACR.

Responses to low levels of oxygen (hypoxia) are essential to maintain homeostasis. During the hypoxic response, gene expression is altered by various transcription factors. The transcription factor, hypoxia-inducible factor (HIF), plays a central role in the hypoxic response. The α subunit of HIF, which is actively degraded during normoxia, becomes stabilized during hypoxia, which leads to HIF activation. A microarray analysis of HeLa cells showed that expression of matrix metalloproteinase 1 (MMP1) was markedly induced during prolonged hypoxia. CREB and NF-κB binding sites were identified in the MMP1 promoter region between 1945 and 1896 nucleotides upstream of the transcription start site. Assays with luciferase reporters demonstrated that HIF activity was induced during the early phase of hypoxia, whereas CREB and NF-κB were activated during the later (prolonged) phase. Depletion of CREB and/or NF-κB reduced MMP1 induction during prolonged hypoxia both at the mRNA and protein levels. A chromatin immunoprecipitation assay demonstrated binding of CREB and NF-κB to the MMP1 promoter. Finally, cell migration and invasion on a collagen matrix and pulmonary metastasis in nude mice were inhibited after depletion of CREB and NF-κB in MDA-MB-231 cells. Taken together, these results suggest that the cooperative action of CREB and NF-κB plays an important role to induce MMP1 expression during prolonged hypoxia and regulates cell migration and invasion in cancer cells.

Cells induce the hypoxia responses to adapt to the environment when organisms are exposed to a low oxygen environment. The hypoxia response leads to the activation of multiple cellular signalling pathways involved in regulation of respiration, metabolism, cell survival and so forth. Hypoxia-Inducible-Factor (HIF) pathway plays a central role during the hypoxia response as its expression and activity are regulated in an oxygen-dependent manner and it also regulates the expression of multiple hypoxia responsive genes. The expression of HIF is regulated by proline hydroxylation, which is mediated by HIF prolyl-hydroxylase named PHD. The hydroxylated HIF-α subunit is degraded via the ubiquitin–proteasome pathway. The PHD activity needs to be strictly regulated to ensure the stabilization of HIF under hypoxic conditions, because PHD leads to HIF degradation. This review describes the regulatory mechanism of HIF stability and activity under normoxia and hypoxic conditions. Furthermore, the role of the HIF-independent pathways during the hypoxia response, which is as important as the HIF pathway, will also be described.