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 TGF-β 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 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 non-small cell lung cancer (NSCLC) cells and correlates with poor prognosis in lung cancer patients. Our findings uncover an uncharacterized mechanism underlying the local effect of FH on TGF-β induced-gene transcription, on which the inhibitory effect from PAK4 promotes tumorigenesis in lung cancer.