CEP135 isoform dysregulation promotes centrosome amplification in breast cancer cells

Abstract

The centrosome, composed of two centrioles surrounded by pericentriolar material, is the cell’s central microtubule-organizing center. Centrosome duplication is coupled with the cell cycle such that centrosomes duplicate once in S phase. Loss of such coupling produces supernumerary centrosomes, a condition called centrosome amplification (CA). CA promotes cell invasion and chromosome instability, two hallmarks of cancer. We examined the contribution of centriole overduplication to CA and the consequences for genomic stability in breast cancer cells. CEP135, a centriole assembly protein, is dysregulated in some breast cancers. We previously identified a short isoform of CEP135, CEP135mini, that represses centriole duplication. Here, we show that the relative level of full-length CEP135 (CEP135full) to CEP135mini (the CEP135full:mini ratio) is increased in breast cancer cell lines with high CA. Inducing expression of CEP135full in breast cancer cells increases the frequency of CA, multipolar spindles, anaphase-lagging chromosomes, and micronuclei. Conversely, inducing expression of CEP135mini reduces centrosome number. The differential expression of the CEP135 isoforms in vivo is generated by alternative polyadenylation. Directed genetic mutations near the CEP135mini alternative polyadenylation signal reduces the CEP135full:mini ratio and decreases CA. We conclude that dysregulation of CEP135 isoforms promotes centriole overduplication and contributes to chromosome segregation errors in breast cancer cells.

The Yin and Yang of Autosomal Recessive Primary Microcephaly Genes: Insights from Neurogenesis and Carcinogenesis

“…MCPH gene overexpression is always associated with centriole overduplication, multipolar spindles, anaphase-lagging chromosomes, and micronuclei. MCPH4, MCPH7, MCPH8, MCPH10, MCPH13, MCPH17, MCPH19, and MCPH23 are highly expressed in different tumor tissues or cancer cell lines, indicating that some MCPH genes can be considered as oncogenes or potential cancer biomarkers [24][25][26][27][28][29][30][31]. The knockdown or inhibited expression of these genes may be a potential therapeutic method for cancer treatment [31][32][33].…”

“…Assembly of centrosome and microtubule [63] Centriole duplication (breast cancer) [29] Establishment of centrosome asymmetry [64] MCPH10 (ZNF335) Neural progenitor self-renewal, neurogenesis, and neuronal differentiation [65] tumor progression (Bladder cancer) [24] MCPH12 (CDK6)…”

“…In the Drosophila nervous system, the central protein BLD10/MCPH8 is vital to the establishment of centrosome asymmetry in Drosophila neuroblasts [64]. In breast cancer, mutations in MCPH8 promote centriole overduplication, leading to chromosome segregation errors in breast cancer cells [29]. MCPH9 (CEP152) acts as a scaffold and is essential for centriole expansion and spindle formation [100].…”

WBP11 is required for splicing the TUBGCP6 pre-mRNA to promote centriole duplication

“…Expression of the centriole proteins PLK4 and CP110 is downregulated by the binding of miRNAs to the 39 UTR of the mRNA (Bao et al, 2018;Cao et al, 2012;Song et al, 2014). Moreover, two alternative isoforms of CEP135 have been shown to play opposing roles in centriole biogenesis, and dysregulation of isoform expression promotes centrosome amplification in breast cancer cells (Dahl et al, 2015;Ganapathi Sankaran et al, 2019). A genome-wide RNAi screen revealed a strong connection between splicing factors and centriole biology, with 14 of 38 genes required for centriole biogenesis playing established roles in mRNA splicing (Balestra et al, 2013).…”

Primary microcephaly with an unstable genome

“…Increased centriole number and more aggressive(Sankaran et al 2019) MCPH9/CEP152 Overexpression in cancer cells of adrenocortical carcinoma, brain lower grade glioma, kidney chromophobe, mesothelioma, pheochromocytoma and paragan-glioma Poor prognosis (data obtained from TCGA database and analyzed by UALCAN*) Decreased expression level in cancer cells of head and neck squamous cell carcinoma, rectum adenocarcinoma and thymoma Poor prognosis (data obtained from TCGA database and analyzed by UALCAN*) MCPH10/ZNF335 Up-regulation in bladder cancer Enhance tumor cell aggressive and poor prognosis (Frantzi et al 2013) MCPH11/PHC1 Overexpression in cancer cells of adrenocortical carcinoma and colon adenocarcinoma Poor prognosis (data obtained from TCGA database and analyzed by UALCAN*) Decreased expression level in cancer cells of pancreatic adenocarcinoma Poor prognosis (data obtained from TCGA database and analyzed by UALCAN*) MCPH12/CDK6 Overexpressed in lymphoma, leukemia, glioma, glioblastoma, medulloblastoma, and cancers of squamous cells, salivary gland, bladder, pancreas and prostate Associated with poor prognosis in hematological malignancies and medulloblastoma (Tadesse et al 2015)…”