Abstract


PHF14 inhibits neuroendocrine tumor proliferation and predicts responsivity to the PDGFR inhibitor Sunitinib

Dongyun Zhang1, Ph.D., Anthony Heaney1, 2, M.D., PhD.
Departments of 1 Medicine and 2 Neurosurgery, David Geffen School of Medicine, University of California, Los Angeles, California

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PHF14 inhibits neuroendocrine tumor proliferation and predicts responsivity to the PDGFR inhibitor Sunitinib

Dongyun Zhang1, Ph.D., Anthony Heaney1, 2, M.D., PhD.
Departments of 1 Medicine and 2 Neurosurgery, David Geffen School of Medicine, University of California, Los Angeles, California

Histone modifications dynamically regulate chromatin landscaping and DNA damage/repair, replication and transcription, and deregulation of this epigenetic mechanism plays an important role in the pathogenesis of human cancers. The plant homeodomain finger (PHF) superfamily functions as essential reader/effector of histone marks and translates the histone modification codes into biological consequences. PHF14 is a recently identified histone binding partner, but its role in tumorigenesis remains largely unknown. In recent genomic studies, we observed a mutation in PHF14 in a neuroendocrine tumor. We therefore sought to use shRNA-directed knock-down and CRISPR/Cas9-based knock-out approaches to deplete PHF14 expression and understand the function of this mutation using human neuroblastoma SHSY-5Y cells. We demonstrated that PHF14 depletion promoted neuroblastoma cell proliferation and increased colony formation in soft agar. Concomitant with the upregulation of proliferation rates in the PHF14 depleted cells, we observed increased platelet derived growth factor (PDGFR)-alpha mRNA and protein expression in PHF14 knock-down and knock-out cells. To test if PHF14 loss altered the responsiveness to PDGFR-directed tyrosine kinase inhibitors, PHF14 knock-down and control SHSY-5Y cells were treated with Sunitinib. Sunitininb (5 μM) resulted in a 30% more suppression of proliferation in the PHF-14 knock-down cells compared to control cells (Proliferation Fold Change, Control, 0.44±0.1 vs. shRNA PHF14, 0.25±0.02, p<0.05). Similar increases in sensitivity to Sunitinib treatment were observed in PHF14 knock-down murine pheochromocytoma PC12 cells, indicating the broader role of PHF14 as a prognostic biomarker for Sunitinib treatment response in patents with neuroendocrine tumors.

In conclusion, reduced PHF14 expression promotes neuroendocrine tumor proliferation and sensitizes tumor cell response to treatment with the PDGFR inhibitor Sunitinib. These findings indicate a potential role for PHF14 as a predictor of Sunitinib responsiveness in neuroendocrine tumors.

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