FGF-2 Disrupts Mitotic Stability in Prostate Cancer through the Intracellular Trafficking Protein CEP57

Abstract

Malignant tumors with deregulated FGF-2 expression such as prostate cancer are also frequently aneuploid. Aneuploidy can be caused by cell division errors due to extra centrosomes and mitotic spindle poles. However, a link between FGF-2 overexpression and chromosome missegregation has so far been elusive. Here, we show that FGF-2 rapidly uncouples centrosome duplication from the cell division cycle in prostate cancer cells through CEP57, an intracellular FGF-2-binding and trafficking factor. CEP57 was initially identified as a regulator of centriole overduplication in an RNA interference screen. We subsequently found that CEP57 rapidly stimulates centriole overduplication and mitotic defects when overexpressed and is required not only for FGF-2-induced centriole overduplication but also for normal centriole duplication. We provide evidence that CEP57 functions by modulating tubulin acetylation, thereby promoting daughter centriole stability. CEP57 was found to be overexpressed on the mRNA and protein level in a subset of prostate cancers, of which the vast majority also showed FGF-2 upregulation. Taken together, our results show an unexpected link between altered microenvironmental signaling cues such as FGF-2 overexpression and mitotic instability and provide a rationale for the therapeutic targeting of the FGF-2/FGFR1/CEP57 axis in prostate cancer. Cancer Res; 73(4);

Host Age Is a Systemic Regulator of Gene Expression Impacting Cancer Progression

“…These 4, all tumor promoters (22, 31–33), were predicted to be significantly inhibited in old mice. Both FGF2 (31) and ANGPT2 (32) are angiogenesis-associated factors, whereas IL5 is involved in angiogenesis and immune response (34, 35) and TGFβ1 in many functions including vascular development and angiogenesis (36). FGF2 has also been shown to induce proliferation of fibroblasts through TGFβ1 signaling, which affects extracellular matrix (ECM) production (37).…”

Cep70 regulates microtubule stability by interacting with HDAC6

“…The centrosomal protein CEP57 has been found to promote daughter centriole stability by modulating tubulin acetylation [33]. The Chlamydomonas homolog of Cep70, CRC70, promotes centriole assembly by recruiting spindle assembly abnormal protein 6 (SAS‐6) and Bld10p [16].…”

Cep57 Protein Is Required for Cytokinesis by Facilitating Central Spindle Microtubule Organization

“…Cep57 has also been reported to be required for spindle pole integrity (16). In addition, a recent study reported that Cep57 is related to prostate cancer and is required for centriole duplication (32). Therefore, Cep57 regulates the cell cycle at multiple stages to ensure correct segregation of the genetic material during mitosis.…”