Loss-of-function mutations of fumarate hydratase are found in hereditary leiomyomatosis and renal cell carcinoma. Accumulation of fumarate promotes tumorigenesis primarily through which mechanism?

• A Inhibition of prolyl hydroxylase, stabilizing HIF-1alpha under normoxia ✓
• B Activation of AMPK leading to suppression of mTORC1
• C Direct inhibition of histone lysine demethylases only, mimicking 2-hydroxyglutarate
• D Covalent modification of pyruvate dehydrogenase, forcing complete oxidative metabolism

Explanation

Accumulated fumarate, like succinate from SDH mutations, inhibits alpha-ketoglutarate-dependent dioxygenases including prolyl hydroxylases that mark HIF-1alpha for degradation. Stabilized HIF-1alpha drives angiogenesis and glycolytic adaptation even in normoxia, a pseudohypoxic drive. Fumarate also inhibits other alpha-KG dioxygenases, but option C is wrong because it says 'only', and the pseudohypoxic HIF mechanism is the primary tumorigenic route.

Reference: Robbins and Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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