The metabolic activity of fumarase (FH) participates in gene transcription linking to tumor cell growth. However, whether this effect is implicated in lung cancer remains unclear. Here, we show TGFβ induces p38-mediated FH phosphorylation at Thr 90, which leads to a FH/CSL (also known as RBP-Jκ)/p53 complex formation and FH accumulation at p21 promoter under concomitant activation of Notch signaling; in turn, FH inhibits histone H3 Lys 36 demethylation and thereby promotes p21 transcription and cell growth arrest. In addition, FH is massively phosphorylated at the Ser 46 by PAK4 in non-small cell lung cancer (NSCLC) cells, and PAK4-phosphorylated FH binds to 14-3-3, resulting in cytosolic detention of FH and prohibition of FH/CSL/p53 complex formation. Physiologically, FH Ser 46 phosphorylation promotes tumorigenesis through its suppressive effect on FH Thr 90 phosphorylation-mediated cell growth arrest in NSCLC cells and correlates with poor prognosis in patients with lung cancer. Our findings uncover an uncharacterized mechanism underlying the local effect of FH on TGFβ-induced gene transcription, on which the inhibitory effect from PAK4 promotes tumorigenesis in lung cancer. SIGNIFICANCE: Fumarase counteracts CSL via its metabolic activity to facilitate TGFβ-induced cell growth arrest, an effect largely blocked by PAK4-mediated phosphorylation of fumarase.
©2019 American Association for Cancer Research.