Haploinsufficiency of the ESCRT Component HD-PTP Predisposes to Cancer.

Sanaz Manteghi, Marie-Claude Gingras, Dmitri Kharitidi, Luc Galarneau, Maud Marques, Ming Yan, Regina Cencic, Francis Robert, Marilène Paquet, Michael Witcher, Jerry Pelletier, Arnim Pause

Cell reports 2016 May 31

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Endosomal sorting complexes required for transport (ESCRT) drive cell surface receptor degradation resulting in attenuation of oncogenic signaling and pointing to a tumor suppressor function. Here, we show that loss of function of an ESCRT protein (HD-PTP encoded by the PTPN23 gene, located on the tumor suppressor gene cluster 3p21.3) drives tumorigenesis in vivo. Indeed, Ptpn23(+/-) loss predisposes mice to sporadic lung adenoma, B cell lymphoma, and promotes Myc-driven lymphoma onset, dissemination, and aggressiveness. Ptpn23(+/-)-derived tumors exhibit an unaltered remaining allele and maintain 50% of HD-PTP expression. Consistent with the role of HD-PTP in attenuation of integrin recycling, cell migration, and invasion, hemizygous Ptpn23(+/-) loss increases integrin β1-dependent B cell lymphoma survival and dissemination. Finally, we reveal frequent PTPN23 deletion and downregulation in human tumors that correlates with poor survival. Altogether, we establish HD-PTP/PTPN23 as a prominent haploinsufficient tumor suppressor gene preventing tumor progression through control of integrin trafficking. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

Citation

Sanaz Manteghi, Marie-Claude Gingras, Dmitri Kharitidi, Luc Galarneau, Maud Marques, Ming Yan, Regina Cencic, Francis Robert, Marilène Paquet, Michael Witcher, Jerry Pelletier, Arnim Pause. Haploinsufficiency of the ESCRT Component HD-PTP Predisposes to Cancer. Cell reports. 2016 May 31;15(9):1893-900