SMARCB1 regulates the hypoxic stress response in sickle cell trait

Area of Science:

• Oncology
• Genetics
• Pathophysiology

Background:

• Renal medullary carcinoma (RMC) is an aggressive kidney cancer predominantly affecting individuals with sickle cell trait (SCT).
• Loss of the tumor suppressor gene *SMARCB1* is a hallmark of RMC.
• Sickle cell trait induces chronic renal medullary hypoxia, potentially influencing RMC development.

Purpose of the Study:

• To investigate if loss of *SMARCB1* provides a survival advantage under hypoxic conditions relevant to SCT.
• To elucidate the role of *SMARCB1* in renal cell response to hypoxia.
• To understand the mechanisms behind RMC's resistance to anti-angiogenesis therapies.

Main Methods:

• Studied hypoxia-induced *SMARCB1* degradation in renal cells.
• Compared the growth of *SMARCB1* wild-type and null renal tumors in mouse models with and without SCT-associated mutations.
• Assessed the sensitivity of *SMARCB1*-null tumors to hypoxia-inducing anti-angiogenesis therapy.
• Reconstituted *SMARCB1* expression to evaluate its effect on tumor sensitivity to hypoxia in vitro and in vivo.

Main Results:

• Hypoxia triggers *SMARCB1* degradation, conferring a survival advantage to renal cells.
• *SMARCB1*-wild-type tumors showed more aggressive growth in SCT models due to lower *SMARCB1* levels.
• *SMARCB1*-null RMC tumors were resistant to hypoxia-based anti-angiogenesis therapies.
• Restoring *SMARCB1* re-sensitized tumors to hypoxic stress.

Conclusions:

• *SMARCB1* degradation is a physiological response to hypoxic stress.
• SCT-induced renal medullary hypoxia contributes to the development of *SMARCB1*-negative RMC.
• *SMARCB1* status is crucial for RMC's resistance to anti-angiogenesis treatments.