The role of hypoxia-inducible factor-1 in cancer stem cells

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The role of hypoxia-inducible factor-1 in cancer stem cells

The role of hypoxia-inducible factor-1 in cancer stem cells.   Cancer stem cells (CSCs) are a group of cells with similar characteristics to stem cells, which are related to the occurrence, recurrence, metastasis and anti-chemotherapy of cancer. CSCs are a challenge for cancer treatment. But this challenge can also provide a new direction for clinical treatment.

Hypoxia in the tumor microenvironment usually occurs in advanced cancers and is related to low survival rates and poor prognosis. More and more studies have found that hypoxia can induce cancer cell invasion, metastasis and epithelial-mesenchymal transition (EMT), thereby promoting the stem-type characteristics of cancer cells.

Hypoxia-inducible factor-1 (HIF-1), as a key molecule in the regulation of CSCs by hypoxia, participates in tumor growth, immune evasion, metabolic reprogramming and drug resistance by regulating the transcription of target genes. HIF-1 seems to play an important or even a core role in the generation and maintenance of CSCs, but its clear mechanism remains to be elucidated.

Researchers from the Stem Cell and Cancer Center of Jilin University First Hospital summarized the role and mechanism of HIF-1 in CSCs in order to provide more targets to solve the limitations of clinical tumor treatment.

They believe that HIF-1 is a heterodimer composed of HIF-1α and HIF-1β (Figure 1). Under normoxia (21% O2) conditions, HIF-1 is degraded by the intracellular oxygen-dependent ubiquitin protease degradation pathway, while it is inhibited under hypoxia.HIF-1α is a hypoxia-inducible transcription factor.

Contains two transcription domains (C-TAD and N-TAD) (11,12). C-TAD can interact with co-activators such as CREB binding protein (CBP)/p300 to regulate the transcription of HIF-1α target genes. It is worth noting that HIF-1α must form a heterodimer with HIF-1β in order to perform its biological functions.

HIF-1β is stably expressed in cells and maintains the stability of HIF-1. The structures included in HIF-1α and HIF-1β are basic helix-loop helix and PER-ARNT-SIM domains, which promote DNA binding and dimerization. More and more evidences indicate that HIF-1α, as the active subunit of HIF-1, participates in inducing and maintaining the phenotype of various CSCs.

Figure 1. Schematic diagram of HIF-1α and HIF-1β. Under hypoxic conditions, PI3K/Akt/mTOR pathway and MAPK (RAF/MEK/ERK) pathway regulate the transcriptional activity of HIF-1α. The up-regulated HIF-1α and HIF-1β form a heterodimer, which regulates the expression of HIF-1α target genes with the participation of the co-activator CBP/p300. Under normal conditions, FIH hydroxylates the asparagine (N803) residues in C-TAD to prevent the cooperative combination of CBP/p300 and C-TAD.

The activity of PHD depends on ferrous iron, dioxygen and 2-oxoglutaric acid, which participate in the hydroxylation of HIF-1α. In addition, VHL, a tumor suppressor, regulates the expression of HIF-1α through ubiquitination and proteasome degradation. HIF-1, hypoxia-inducible factor-1; CBP, CREB binding protein; FIH, a factor that inhibits HIF-1; PHD, prolyl hydroxylase; VHL, Von Hippel-Lindau; Ub, ubiquitination; HRE, Hypoxia response element; TAD, transactivation domain.

The role of epigenetic and post-translational modifications of HIF-1 in CSCs

Epigenetic modifications are reversible and heritable changes in gene function without changing the DNA sequence. HIF-1α can be used as a key regulator of genome methylation in hepatocellular carcinoma cells. The presence of the binding site of HIF-1α on methionine adenosyltransferase 2A (MAT2A) can promote the transcription of MAT2A to maintain the demethylation state of the genome. Unfortunately, most of the current research focuses on the genetic modification of HIF-1 downstream target genes or key enzymes. There are few studies on the epigenetic modification of HIF-1 in CSCs.

Post-translational modification is one of the most important regulatory mechanisms for dynamically and reversibly regulating proteins with biological functions. Previous studies have found that lysine methyltransferase G9a can mono- or double-methylate HIF-1α on lysine 674, reducing the transcription of HIF-1α by reducing the TAD activity of HIF-1α Activity and downstream gene expression; at the same time, G9a is reduced in glioblastoma cells, maintaining the activity of HIF-1α, and promoting HIF-1-dependent cell migration. As a small ubiquitin-like modifier (SUMO) protease, small ubiquitin-like modifier protease 1 (SENP1) forms a positive feedback loop with HIF-1α in hepatocarcinoma cells, so that HIF-1α deSUMO and synthesize it under hypoxia. Stable expression, and can promote the production of liver CSCs.

The role of HIF-1 in non-coding RNA associated with CSCs

Coding RNA (ncRNA) is a type of RNA that is transcribed from DNA but not translated into protein. The types of ncRNA include small interfering RNA (siRNA), long ncRNA (lncRNA) and microRNA (miRNA). The up-regulated lncRNA LOC554202 in small cell lung cancer is proportional to miR-31, thereby targeting FIH and promoting the occurrence of acquired gefitinib resistance. miR-31-5p is up-regulated in lung cancer, and induces glycolytic gene expression by regulating the FIH/HIF pathway, and ultimately promotes cell proliferation and tumor growth. miR-21 and miR-184 are also up-regulated in head and neck squamous cell carcinoma, and their tumorigenic mechanism is similar to miR-31.

In the regulation of HIF-1 expression, the cooperation of miRNA and related lncRNA is equally important. The significantly up-regulated lncRNA TUG1 in osteosarcoma can protect the 3’untranslated region of HIF-1α mRNA from miR-143-5p, thereby promoting the metastasis of osteosarcoma. lncRNA MIR31HG is the host gene of miR-31, located in the first intron of MIR31HG, and has a consistent transcriptional regulatory effect. Studies have found that MIR31HG is a hypoxia-induced lncRNA and acts as a synergist of HIF-1α to regulate the HIF-1 transcription network. In terms of mechanism, MIR31HG directly interacts with HIF-1α to promote the recruitment of HIF-1α and p300 to target gene promoters. It is worth noting that although the expression of MIR31HG is positively correlated with miR-31 in some types of cancer, the knockout of MIR31HG has no effect on miR-31, indicating that the tumor regulation effect of MIR31HG may not be related to miR-31.

Although there are only a few studies on HIF-1 related ncRNA, the existing independent research is sufficient to show that HIF-1 is an important regulator or participant of CSC-related ncRNA (Table 1), which can be eradicated by targeting ncRNA or HIF-1 CSCs prolong the life of patients.

The role of HIF-1 in CSC markers

Studies have found that HIF-1 directly binds to the CD47 promoter to promote gene transcription, which helps to escape the phagocytosis of macrophages and maintain the dry phenotype of breast CSCs. Endogenous HIF-1α is recruited to the CD24 promoter to promote the expression of CD24, as well as tumor formation and metastasis. HIF-1α seems to bind to the CD133 promoter and promote the production of CD133+ glioblastoma, colon and pancreatic CSCs through OCT4 and SOX2. In addition, it has been found that HIF-1α and CD133 are related in the cytoplasm, but not in other parts of the cell, such as the glandular cavity. In turn, CD133 promotes the expression of HIF-1α and transfers it to the nucleus under hypoxia.

The role of HIF-1 in tumor immunity of CSCs

During the EMT process, the author believes that in addition to inducing cancer stemness, immunosuppression can also be observed, which can lead to increased malignancy, drug resistance and metastasis of tumors. Studies have found that hypoxia can further increase the production of immunosuppressive factors, inhibit the phagocytosis of monocytes, inhibit the proliferation of T cells, and activate and induce Tregs of CSCs related to glioma pleomorphism. This may be through phoshphorylated STAT3/ HIF-1α/vascular endothelial growth factor (VEGF) pathway is achieved.

During the EMT process of HIF-1α-induced liver cancer cells, the up-regulated cytokine CCL20 promotes the expression of indoleamine 2,3-dioxygenase in monocyte-derived macrophages, thereby inhibiting the activation and proliferation of T cells, and Induces Tregs by increasing the degradation of tryptophan. Immune escape and immunosuppression are equally important to the existence of CSCs. One of the marker proteins of breast CSC, CD47, can bind to the signal-regulating protein α on the surface of macrophages to avoid phagocytosis by macrophages, and the induction of CD47 depends on the direct regulation of HIF-1α. There are two types of tumor-associated macrophages, M1 and M2, which inhibit or promote tumor growth, respectively.

Type M2 is more common in the tumor microenvironment and promotes tumor invasion. Hypoxia will induce nuclear factor-κB (NF-κB) and HIF-1α successively, leading to the infiltration of M2 macrophages in the tumor microenvironment and the occurrence of tumors. Compared with normal cells, triple-negative breast cancer cells have more HIF-1α-specific IgG, which indicates that HIF-1α is immunogenic. The use of HIF-1α vaccine therapy can recruit type I T cells into tumor tissues, and effectively inhibit basal-like breast CSCs, which can inhibit tumor metastasis. In order to adapt to chronic hypoxia, CD8+ T cells will increase the expression of active HIF-1α and increase their own effector functions.

In addition, the author also introduced the role of HIF-1 in the signaling pathways related to CSCs, and pointed out that HIF-1α interacts with multiple signaling pathways to promote self-expression and participates in maintaining the dry characteristics of CSCs (see Table 2 below) .

Potential goals of CSC treatment

The author believes that the regulatory role of HIF-1 is also different in certain types of cancer (Table 3). Since HIF-1/HIF-1α is a key factor in regulating CSCs, its inhibitors can be used in adjuvant therapy. Acriflavine is a HIF-1 inhibitor that prevents the dimerization of HIF-1α and HIF-1β.

Targeted inhibition of HIF-1 by siRNA can improve the radiotherapy sensitivity of malignant gliomas, but the delivery efficiency of siRNA is limited and still needs to be resolved. The HIF-1α vaccine is proposed to inhibit breast cancer metastasis from the perspective of tumor immunity.

Not only that, the combination of HIF-1α and co-activators can also become a potential therapeutic target. Even under hypoxic conditions, 3-(5′-hydroxymethyl-2′-furyl)-1-benzylindazole can stimulate the effect. In addition, the inhibition of key enzymes and signal pathways (Table 2), key gene knockout, and CSC-related immune and metabolic regulation all constitute potential targets for CSC therapy (Table 4).

Sum up

The author believes that CSCs are a group with differentiation and self-renewal potential, and are involved in tumor metastasis, recurrence and treatment resistance. Understanding the mechanism by which CSCs produce and maintain stemness may help overcome the limitations of clinical cancer treatment.

Hypoxia regulates angiogenesis, tumor formation, immune response, cancer recurrence and metastasis, and participates in the progression of EMT and the production of CSC. HIF-1, which is stably expressed under hypoxic conditions, binds to the HRE on the promoters of key genes to regulate glycolysis, angiogenesis, cell apoptosis, tissue invasion and pH regulation. As the active subunit of HIF-1, HIF-1α is the main transcriptional regulator of the hypoxic adaptive response.

Therefore, this review focuses more on the role of HIF-1α in CSCs, rather than HIF-1, in order to learn from epigenetic changes, immune response, metabolic reprogramming, stem cell markers, and ncRNA and signaling pathways related to CSCs. Propose a new method to eradicate CSCs from multiple perspectives (Figure 2).

Current tumor treatment methods, combined with adjuvant therapy centered on HIF-1/HIF-1α, can prevent the recurrence and metastasis of cancer cells, ultimately increase the cure rate and prolong the lives of patients.

Figure 2. Hypoxia regulates CSCs with HIF-1 as the core. HIF-1α and HIF-1β form a heterodimer, which binds to the HRE on the target gene and activates transcription, which can be inhibited by the inhibitor of HIF-1α-Criefflin.

This figure attempts to show the role and regulation of HIF-1 in CSCs from multiple directions, including epigenetic modification, signaling pathways, non-coding RNA, stem cell markers, immunity and metabolic reprogramming.

CSCs, cancer stem cells; HIF-1, hypoxia-inducible factor-1; SUMO, small ubiquitin-like modification; Ub, ubiquitination; P, phosphorylation; Met, methylation; HRE, hypoxia response element. OXPHOS, oxidative phosphorylation; CBP, CREB binding protein; NK, natural killer; KLF4, Krüppel-like factor 4; ALDH1A1,4-trimethylaminobutyraldehyde dehydrogenase

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