Lunenfeld Tanenbaum Research Institute, Sinai Health System, Toronto, ON, M5G 1X5, Canada.
Department of Surgical Oncology, University of Toronto, Toronto, ON, M5G 2M9, Canada.
Commun Biol. 2020 Aug 17;3(1):448. doi: 10.1038/s42003-020-01161-3.
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.
Polo 样激酶 4（Plk4）是一种受到严格调控的丝氨酸/苏氨酸激酶，它控制着中心体的复制。在许多常见的人类癌症中，Plk4 的表达增加，导致中心体过度复制、有丝分裂异常和染色体不稳定。Plk4 还可以通过调节肌动蛋白细胞骨架促进癌症的侵袭和转移。在这里，我们证明了 Plk4 与 FAM46C/TENT5C 的物理相互作用，FAM46C/TENT5C 是一种保守的蛋白，直到最近才具有未知的功能。FAM46C 定位于中心体，抑制 Plk4 激酶活性，并抑制 Plk4 诱导的中心体复制。FAM46C 通过 Plk4 功能的干扰独立于后者的核苷酸转移酶活性。此外，FAM46C 抑制了 MDA MB-435 细胞在异种移植模型中的侵袭，并抑制了癌症的生长，这与 Plk4 的作用相反。我们在源自患者的结直肠癌肿瘤组织中证明了 FAM46C 的缺失，随着临床分期的进展，这种缺失变得更加明显。这些结果表明 FAM46C 是一种肿瘤抑制因子，通过抑制 Plk4 的活性发挥作用。
