FAM46C/TENT5C functions as a tumor suppressor through inhibition of Plk4 activity

Karineh Kazazian,Julie Tan,Roland Xu,Wendy Johnston,Chae Min Michelle Lee,Hannah Sun-Tsi Wu,Karina Pacholzyk,Francis Si-Wah Zih,Yosr Haffani,Minji Kim,Carol Jane Swallow,Alannah Smrke,Deanna Ng,Aaron Pollett

doi:10.1038/s42003-020-01161-3

Abstract

Polo like kinase 4 (Plk4) is a tightly regulated serine threonine kinase that governs centriole duplication. Increased Plk4 expression, which is a feature of many common human cancers, causes centriole overduplication, mitotic irregularities, and chromosomal instability. Plk4 can also promote cancer invasion and metastasis through regulation of the actin cytoskeleton. Herein we demonstrate physical interaction of Plk4 with FAM46C/TENT5C, a conserved protein of unknown function until recently. FAM46C localizes to centrioles, inhibits Plk4 kinase activity, and suppresses Plk4-induced centriole duplication. Interference with Plk4 function by FAM46C was independent of the latter’s nucleotidyl transferase activity. In addition, FAM46C restrained cancer cell invasion and suppressed MDA MB-435 cancer growth in a xenograft model, opposing the effect of Plk4. We demonstrate loss of FAM46C in patient-derived colorectal cancer tumor tissue that becomes more profound with advanced clinical stage. These results implicate FAM46C as a tumor suppressor that acts by inhibiting Plk4 activity.

Highlights

Polo like kinase 4 (Plk4) is a tightly regulated serine threonine kinase that governs centriole duplication
We show for the first time that unlike other centriolar Plk[4] interactors, FAM46C is depleted in human colorectal cancer tumor tissue, compared with paired normal mucosa samples taken from the same patient
While FAM46A and FAM46D interacted with several other proteins in yeast 2– hybrid (Y2H) screens (Supplementary Fig. 1d;46,47), they did not interact with Plk[4]

Summary

Introduction

Polo like kinase 4 (Plk4) is a tightly regulated serine threonine kinase that governs centriole duplication. While germline Plk[4] haploidy is insufficient to suppress tumor development in adult life[17], inhibition of Plk[4] kinase activity reduces cancer cell proliferation and migration[5,9,18], indicating a potential for oncogenic function. In keeping with the latter, Plk[4] depletion from malignant cells inhibits tumor progression in xenograft models[9,19], while upregulation of Plk[4] can promote tumorigenesis in vivo[13,16,20]. In a mouse xenograft model of human cancer using

Methods

Results

Conclusion