PAK4 Phosphorylates Fumarase and Blocks TGFβ-Induced Cell Growth Arrest in Lung Cancer Cells

Abstract

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 TGFb induces p38-mediated FH phosphorylation at Thr 90, which leads to a FH/CSL (also known as RBP-Jk)/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 PAK4phosphorylated 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 TGFb-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 TGFb-induced cell growth arrest, an effect largely blocked by PAK4-mediated phosphorylation of fumarase.

Landscape of Genetic and Modular Networks Between Non-Small Cell Lung Cancer and Chronic Obstructive Pulmonary Disease

“…Positive correlation between MMP9 and COPD assessment test score in COPD patients was previously demonstrated [12] . TP53 mutation occurs in many human malignancies and is involved in cell apoptosis, senescence and DNA repair [13] . The expression of mutant TP53 is associated with platinum-based chemo-resistant [14] .…”

“…The terms ''non small cell lung cancer" or "chronic obstructive pulmonary disease" were inputted into to the search box of the Online Mendelian Inheritance in Man (OMIM) database, (http://www.ncbi.nlm.nih.gov/omim), a knowledge database of human genes and genetic disorders (13).…”

Coordinated dysregulation of cancer progression by the HER family and p21-activated kinases

“…Because several phosphoproteomic databases have reported the presence of phosphorylated H4-Thr80 in higher eukaryotes [132,133], a similar operating mechanism may exist in cancer cells. Evidence also suggests that PAK4mediated phosphorylation of fumarase, a metabolic enzyme, at Ser46 facilitates its cytoplasmic retention and antagonizes TGF-β-mediated inhibition of lung cancer cells [134]. Because fumarase is also important in DNA repair as it controls the status of H3K36me2 at the proximity of DNA breaks [135]), whether PAK-mediated regulation of fumarase could modify its role in DNA repair remains unclear.…”

Functions of metabolic enzymes in the development of non‐small cell lung cancer

“…It can bind to Bub3 (a spindle checkpoint protein) and phosphorylate it at Tyr207 enabling the interaction of the Bub3‐Bub1 complex with kinetochores, which is necessary for the mitotic checkpoint and tumorigenesis . Moreover, FH localized in the nucleus promotes driver gene‐mediated transcription by inhibiting H3K36me2 demethylation, and thereby promotes the proliferation of NSCLC cells …”