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Hypoxia Selectively Increases a SMAD3 Signaling Axis to Promote Cancer Cell Invasion
Karine Brochu-Gaudreau1, Martine Charbonneau1, Kelly Harper1
1Department of Immunology and Cell Biology, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada.
Abstract:
Transforming growth factor β (TGFβ) plays a paradoxical role in cancer, first inhibiting then promoting its progression, a duality that poses a real challenge for the development of effective TGFβ-targeted therapies. The major TGFβ downstream effectors, SMAD2 and SMAD3, display both distinct and overlapping functions and accumulating evidence suggests that their activation ratio may contribute to the dual effect of TGFβ. However, the mechanisms responsible for their selective activation remain poorly understood. Here, we provide experimental evidence that hypoxia induces the pro-invasive arm of TGFβ signaling through a selective increase in SMAD3 interaction with SMAD-Anchor for Receptor Activation (SARA). This event relies on HDAC6-dependent SMAD3 bioavailability, as well as increased SARA recruitment to EEA1+ endosomes. A motility gene expression study indicated that SMAD3 selectively increased the expression of ITGB2 and VIM, two genes that were found to be implicated in hypoxia-induced cell invasion and associated with tumor progression and metastasis in cohorts of cancer patients. Furthermore, CAM xenograft assays show the significant benefit of selective inhibition of the SMAD3 signaling pathway as opposed to global TGFβ inhibition in preventing tumor progression. Overall, these results suggest that fine-tuning of the pro-invasive HDAC6-SARA-SMAD3 axis could be a better strategy towards effective cancer treatments.
Insights
Hypoxia promotes cancer invasion by selectively activating SMAD3 signaling via HDAC6 and SARA. Targeting this specific pathway, rather than general TGFβ, shows promise for effective cancer therapies.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Signaling
Background:
- Transforming growth factor β (TGFβ) has a dual role in cancer, initially inhibiting then promoting tumor progression, complicating targeted therapies.
- The downstream effectors SMAD2 and SMAD3 have distinct and overlapping functions, and their activation ratio may influence TGFβ's dual role.
- Mechanisms driving selective SMAD activation remain unclear, hindering therapeutic development.
Purpose of the Study:
- To investigate the mechanisms by which hypoxia selectively activates the pro-invasive TGFβ signaling pathway.
- To elucidate the role of SMAD3, SARA, and HDAC6 in hypoxia-induced cancer cell invasion.
- To evaluate the therapeutic potential of selectively inhibiting the SMAD3 pathway in cancer.
Main Methods:
- Experimental investigation of SMAD3 interaction with SMAD-Anchor for Receptor Activation (SARA) under hypoxic conditions.
- Assessment of HDAC6-dependent SMAD3 bioavailability and SARA recruitment to endosomes.
- Analysis of motility gene expression (ITGB2, VIM) and its association with hypoxia-induced invasion.
- Evaluation of therapeutic efficacy using CAM xenograft assays with selective SMAD3 inhibition versus global TGFβ inhibition.
Main Results:
- Hypoxia selectively enhances SMAD3 interaction with SARA, promoting pro-invasive TGFβ signaling.
- HDAC6-dependent SMAD3 bioavailability and increased SARA recruitment to EEA1+ endosomes are crucial for this process.
- SMAD3 selectively upregulates ITGB2 and VIM expression, genes linked to hypoxia-induced invasion, tumor progression, and metastasis.
- Selective inhibition of the SMAD3 pathway significantly reduces tumor progression in xenograft models, outperforming global TGFβ inhibition.
Conclusions:
- Hypoxia drives cancer invasion through a selective HDAC6-SARA-SMAD3 signaling axis.
- Targeting the pro-invasive SMAD3 pathway offers a more effective therapeutic strategy than broad TGFβ inhibition.
- Fine-tuning the HDAC6-SARA-SMAD3 axis presents a promising avenue for developing novel cancer treatments.
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