PAK2–c-Myc–PKM2 axis plays an essential role in head and neck oncogenesis via regulating Warburg effect

Abstract

The histone modifiers (HMs) are crucial for chromatin dynamics and gene expression; however, their dysregulated expression has been observed in various abnormalities including cancer. In this study, we have analyzed the expression of HMs in microarray profiles of head and neck cancer (HNC), wherein a highly significant overexpression of p21-activated kinase 2 (PAK2) was identified which was further validated in HNC patients. The elevated expression of PAK2 positively correlated with enhanced cell proliferation, aerobic glycolysis and chemoresistance and was associated with the poor clinical outcome of HNC patients. Further, dissection of molecular mechanism revealed an association of PAK2 with c-Myc and c-Myc-dependent PKM2 overexpression, wherein we showed that PAK2 upregulates c-Myc expression and c-Myc thereby binds to PKM promoter and induces PKM2 expression. We observed that PAK2–c-Myc–PKM2 axis is critical for oncogenic cellular proliferation. Depletion of PAK2 disturbs the axis and leads to downregulation of c-Myc and thereby PKM2 expression, which resulted in reduced aerobic glycolysis, proliferation and chemotherapeutic resistance of HNC cells. Moreover, the c-Myc complementation rescued PAK2 depletion effects and restored aerobic glycolysis, proliferation, migration and invasion in PAK2-depleted cells. The global transcriptome analysis of PAK2-depleted HNC cells revealed the downregulation of various genes involved in active cell proliferation, which indicates that PAK2 overexpression is critical for HNC progression. Together, these results suggest that the axis of PAK2–c-Myc–PKM2 is critical for HNC progression and could be a therapeutic target to reduce the cell proliferation and acquired chemoresistance and might enhance the efficacy of standard chemotherapy which will help in better management of HNC patients.

Quantitative SWATH-Based Proteomic Profiling for Identification of Mechanism-Driven Diagnostic Biomarkers Conferring in the Progression of Metastatic Prostate Cancer

“…Studies have shown elevated expression of PAK2 resulting in an alteration of histone modification, thereby regulating gene expressions also. Differential expression levels of PAK2 have been reported in various malignancies including breast, gastric, hepatocarcinoma and head, and neck cancer (28,29). Elevated levels of PAK2 have been reported in castration-resistant tumors and the knockdown experiments further revealed that PAK2 can regulate colony formation and invasion experiment.…”

Simvastatin re-sensitizes hepatocellular carcinoma cells to sorafenib by inhibiting HIF-1α/PPAR-γ/PKM2-mediated glycolysis

“…Moreover, the oncogene Myc, which includes c-Myc, N-Myc, and L-Myc, plays an important role in aerobic glycolysis in HCC as well. C-Myc is reported to overexpressed in HCC, and can promote the Warburg effect by increasing the expression of glycolytic related markers, such as GLUT1, LDH and PKM2 [66][67][68][69]. Conversely, c-Myc can also be regulated by PKM2 in the nucleus, for PKM2 can translocate into nucleus and act as a coactivator of β-catenin to induce c-Myc expression, leading to the expression of c-Myc targeted genes [30,67].…”

Molecular prognosticators in clinically and pathologically distinct cohorts of head and neck squamous cell carcinoma—A meta-analysis approach

“…(with prognostic efficacy), all of which were previously identified to play a major role in head and neck oncogenesis as well as in other cancers [45][46][47][48][49][50][51][52] EPS8, identified in ECS-laryngopharyngeal patients in this study, is known to be involved in the proliferation apoptosis, adhesion and migration in other cancers including HNSCC [53][54][55][56]. The correlation of these markers with the clinically/pathologically classified sub-cohorts (ALI+/PNI+) indicated their possible relevance as predictive panel, with a subset of genes providing survival impact.…”