Hypoxia-Inducible Factors: Master Regulators of Cancer Progression

Abstract

Intratumoral hypoxia (reduced O availability) is a common finding in human cancer and leads to increased activity of hypoxia-inducible factors (HIFs), which regulate the expression of genes that contribute to angiogenesis, metabolic reprogramming, extracellular matrix remodeling, epithelial-mesenchymal transition, motility, invasion, metastasis, cancer stem cell maintenance, immune evasion, and resistance to chemotherapy and radiation therapy. Conventional anticancer therapies target well-oxygenated and proliferating cancer cells, whereas there are no approved therapies that target hypoxic cancer cells, despite growing clinical and experimental evidence indicating that intratumoral hypoxia is a critical microenvironmental factor driving cancer progression. In this review, our current understanding of the consequences of HIF activity and the translational potential of targeting HIFs for cancer therapy are discussed.

ARNT/HIF‐1β links high‐risk 1q21 gain and microenvironmental hypoxia to drug resistance and poor prognosis in multiple myeloma

“…To be an active transcription factor, HIF‐1α must form a complex with HIF‐1β. In normoxia, HIF‐1α rapidly turns over via ubiquitin‐proteasome system (UPS), while under hypoxia, it translocates to the nucleus where it forms a heterodimer with HIF‐1β to trigger transcription of target genes 11. Therefore, HIF‐1α is inducible and unstable, while HIF‐1β is often considered to be constitutively expressed.…”

“…Hypoxia triggers various cellular responses primarily via the HIF family 11, 12. HIF is a heterodimeric complex composed of one α (eg, HIF‐1α or HIF‐2α) and one β‐subunit (HIF‐1β) 11.…”

“…Hypoxia triggers various cellular responses primarily via the HIF family 11, 12. HIF is a heterodimeric complex composed of one α (eg, HIF‐1α or HIF‐2α) and one β‐subunit (HIF‐1β) 11. MM microenvironment is featured by hypoxia naturally existing in bone marrow niches where MM cells reside, which plays a critical role in MM cell survival, growth, metabolism, drug resistance, and angiogenesis, etc 13, 14, 15.…”

“…HIF‐1β predominately binds HIF‐1α or aryl hydrocarbon receptor (AhR) to form heterodimer complexes that regulate transcription of target genes involved in various physiological and pathological processes, including cancer. In the former, the role of the HIF‐1 complex consisting of HIF‐1α or ‐2α, a transactivating subunit that is inducible (eg, in response to hypoxia), and HIF1β, a regulatory subunit that is often considered as constitutively expressed and unaffected by hypoxia, has been well documented in tumor progression,11 tumor‐stroma interaction,12 metastasis,10 etc. In the latter, the AhR/ARNT complex binds to dioxin‐responsive elements (DREs) to induce transcription of target genes that encode drug‐metabolizing enzymes (eg, cytochrome P450 1A1) as well as proteins governing cell proliferation, differentiation, and apoptosis, which most likely facilitates carcinogenesis and tumor promotion 16.…”

Hif1α Deletion Limits Tissue Regeneration via Aberrant B Cell Accumulation in Experimental Pancreatitis

“…Specifically, hypoxic stress inhibits normal proteasomal degradation of HIFα subunits (HIF1α and HIF2α), resulting in HIFα protein accumulation. Once stabilized, HIF1α activates the transcription of numerous genes mediating metabolic adaptations, angiogenesis, cell survival, metastasis, and inflammation (Lee and Simon, 2015; Schito and Semenza, 2016). HIF1α protein is detected in multiple inflammatory disorders, such as inflammatory bowel disease and acute lung injury, and has profound effects on disease pathogenesis and outcomes (Palazon et al, 2014).…”