Targeting the SMURF2-HIF1α axis: a new frontier in cancer therapy

Abstract

The SMAD-specific E3 ubiquitin protein ligase 2 (SMURF2) has emerged as a critical regulator in cancer biology, modulating the stability of Hypoxia-Inducible Factor 1-alpha (HIF1α) and influencing a network of hypoxia-driven pathways within the tumor microenvironment (TME). SMURF2 targets HIF1α for ubiquitination and subsequent proteasomal degradation, disrupting hypoxic responses that promote cancer cell survival, metabolic reprogramming, angiogenesis, and resistance to therapy. Beyond its role in HIF1α regulation, SMURF2 exerts extensive control over cellular processes central to tumor progression, including chromatin remodeling, DNA damage repair, ferroptosis, and cellular stress responses. Notably, SMURF2's ability to promote ferroptotic cell death through GSTP1 degradation offers an alternative pathway to overcome apoptosis resistance, expanding therapeutic options for refractory cancers. This review delves into the multifaceted interactions between SMURF2 and HIF1α, emphasizing how their interplay impacts metabolic adaptations like the Warburg effect, immune evasion, and therapeutic resistance. We discuss SMURF2's dual functionality as both a tumor suppressor and, in certain contexts, an oncogenic factor, underscoring its potential as a highly versatile therapeutic target. Furthermore, modulating the SMURF2-HIF1α axis presents an innovative approach to destabilize hypoxia-dependent pathways, sensitizing tumors to chemotherapy, radiotherapy, and immune-based treatments. However, the complexity of SMURF2's interactions necessitate a thorough assessment of potential off-target effects and challenges in specificity, which must be addressed to optimize its clinical application. This review concludes by proposing future directions for research into the SMURF2-HIF1α pathway, aiming to refine targeted strategies that exploit this axis and address the adaptive mechanisms of aggressive tumors, ultimately advancing the landscape of precision oncology.

Keywords: HIF1α; SMURF2; angiogenesis; cancer therapy; ferroptosis; hypoxia; metabolic reprogramming; tumor microenvironment.

Figure 1

A schematic illustration of the interplay between SMURF2, CDK4/6, and HIF-1α in regulating HIF-1α stability in cancer cells. CDK4/6 activity stabilizes HIF-1α, promoting its accumulation, nuclear translocation, and activation of hypoxia-responsive genes. Inhibiting CDK4/6 enhances the interaction between HIF-1α and the E3 ubiquitin ligase SMURF2 leading to HIF-1α ubiquitination and degradation.

Figure 2

Illustration of emerging approaches targeting HIF1α. Various therapeutics inhibit HIF1α signaling by affecting its mRNA expression, protein synthesis, stabilization, dimerization with HIF1β, DNA binding, and transcriptional activity.

Figure 3

The role of differentially expressed proteins in an early-stage, GPX4-independent ferroptosis regulatory mechanism. It emphasizes the central role of the E3 ligase SMURF2 in managing the degradation of GSTP1. The figure also highlights the significance of GST and selenium independent GPx activities of GSTP1 in safeguarding against ferroptosis. Furthermore, it illustrates how manipulating the SMURF2-GSTP1 equilibrium can heighten the vulnerability of cancer cells to ferroptosis.

Figure 4

Molecular mechanisms behind SMURF2’s role as a tumor suppressor SMURF2 modulates various cellular processes, including gene expression, chromatin structure, and the DNA damage response, primarily through the ubiquitin-proteasome-mediated degradation pathway. In the context of chromatin compaction and gene regulation, SMURF2 is involved in the degradation of transcription factors such as YY1 and the histone-modifying enzyme RNF20. The interaction with transcriptional regulators like ID1/ID3, mentioned in the diagram, highlights SMURF2’s role in gene expression modulation. Additionally, as noted in the diagram, SMURF2’s regulatory influence extends to other transcription factors and enzymes, playing a critical role in cellular mechanisms that impact tumor suppression and cancer progression (132).