A dual specificity kinase, DYRK1A, as a potential therapeutic target for head and neck squamous cell carcinoma.

Vishalakshi Nanjappa,Vani Santosh,Gajanan Sathe,Harsha Gowda,Vinuth N Puttamallesh ,Premendu P Mathur,Remya Raja,T S Keshava Prasad,Joseph A Califano,Geethanjali Sukumar,Akhilesh Pandey,Sneha M Pinto,David Sidransky,Ankit Jain ,Sandip Chavan,Annapoorni Rangarajan,Manoj Kumar ,Nandini A Sahasrabuddhe,Sai A Balaji,Aditi Chatterjee,Aneesha Radhakrishnan

doi:10.1038/srep36132

Abstract

Despite advances in clinical management, 5-year survival rate in patients with late-stage head and neck squamous cell carcinoma (HNSCC) has not improved significantly over the past decade. Targeted therapies have emerged as one of the most promising approaches to treat several malignancies. Though tyrosine phosphorylation accounts for a minority of total phosphorylation, it is critical for activation of signaling pathways and plays a significant role in driving cancers. To identify activated tyrosine kinase signaling pathways in HNSCC, we compared the phosphotyrosine profiles of a panel of HNSCC cell lines to a normal oral keratinocyte cell line. Dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A) was one of the kinases hyperphosphorylated at Tyr-321 in all HNSCC cell lines. Inhibition of DYRK1A resulted in an increased apoptosis and decrease in invasion and colony formation ability of HNSCC cell lines. Further, administration of the small molecular inhibitor against DYRK1A in mice bearing HNSCC xenograft tumors induced regression of tumor growth. Immunohistochemical labeling of DYRK1A in primary tumor tissues using tissue microarrays revealed strong to moderate staining of DYRK1A in 97.5% (39/40) of HNSCC tissues analyzed. Taken together our results suggest that DYRK1A could be a novel therapeutic target in HNSCC.

Highlights

We employed tandem mass tag (TMT)-based labeling technology coupled with anti-phosphotyrosine antibody-based enrichment approach to identify differentially phosphorylated proteins between normal oral keratinocyte OKF6/TERT1, and a panel of HNSCC cell lines (JHU-O11, JHU-O22, JHU-O28, JHU-O29, FaDu and CAL 27) (Supplementary Fig. 1)
We identified molecules including protein tyrosine phosphatase, non-receptor type 11 (PTPN11), myelin protein zero-like 1 (MPZL1) and tyrosine kinases such as LYN proto-oncogene (LYN), EPH receptor A2 (EPHA2) and Dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A)
To identify novel therapeutic targets in HNSCC, we studied the phosphotyrosine signaling in a panel of HNSCC cell lines and normal oral keratinocyte cell line OKF6/TERT1

Summary

Introduction

Aberrant activation of kinase driven pathways has been reported to play a crucial role in multiple cellular processes that leads to cancer progression. Such alterations can be assessed by studying the proteome through analysis of the phosphoproteome. We studied the activation of signaling molecules in a panel of HNSCC cell lines and a normal oral keratinocyte cell line (OKF6/TERT1) using phosphoproteomics approach. Dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A) was one of the identified kinases which showed hyperphosphorylation (fold change ≥1.5) in all the 6 HNSCC cell lines compared to normal oral keratinocytes. DYRK1A plays an important role in cell survival by phosphorylating caspase 9 at Thr[125] and inhibiting its action in apoptosis[11]. We have assessed the role of DYRK1A as a potential therapeutic target in HNSCC

Methods

Results

Conclusion