Identification of zinc finger protein of the cerebellum 5 as a survival factor of prostate and colorectal cancer cells

Abstract

Identification of specific drug targets is very important for cancer therapy. We recently identified zinc finger protein of the cerebellum 5 (ZIC5) as a factor that promotes melanoma aggressiveness by platelet‐derived growth factor D (PDGFD) expression. However, its roles in other cancer types remain largely unknown. Here we determined the roles of ZIC5 in prostate cancer (PCa) and colorectal cancer (CRC) cells. Results showed that ZIC5 was highly expressed in CRC and dedifferentiated PCa tissues, whereas little expression was observed in relevant normal tissues. Knockdown of ZIC5 decreased proliferation of several PCa and CRC cell lines with induction of cell death. ZIC5 knockdown significantly suppressed PDGFD expression transcriptionally, and PDGFD suppression also decreased proliferation of PCa and CRC cell lines. In addition, suppression of ZIC5 or PDGFD expression decreased levels of phosphorylated focal adhesion kinase (FAK) and signal transducer and activator of transcription 3 (STAT3) which are associated with PCa and CRC aggressiveness. Furthermore, knockdown of ZIC5 or PDGFD enhanced death of PCa and CRC cells induced by the anti‐cancer drugs docetaxel or oxaliplatin, respectively. These results suggest that ZIC5 and PDGFD promote survival of PCa and CRC cells by enhancing FAK and STAT3 activity, and that the roles of ZIC5 are consistent across several cancer types.

Infiltrating CD4+ T cells attenuate chemotherapy sensitivity in prostate cancer via CCL5 signaling

“…To further study the mechanism of CD4+ T cell and the secreted CCL5 promoting PCa cells chemotherapy‐resistant, we then focused on the STAT3 signaling pathway, a member of the STAT transcription factor family. In PCa, STAT3 activation correlates with Gleason score and pathological stage, promotes tumor invasion and metastasis, is involved in resistance to enzalutamide and Doc . Here, we found that CD4+ T cells might affect PCa chemosensitivity through CCL5 activation of STAT3 via upregulation of STAT3 phosphorylation.…”

β-Catenin/Tcf7l2–dependent transcriptional regulation of GLUT1 gene expression by Zic family proteins in colon cancer

“…In contrast, studies on Zic2 revealed its oncogenic functions in pancreatic cancer ( 30 ), epithelial ovarian cancer ( 31 ), oral squamous cell carcinoma ( 32 ), cervical cancer ( 33 ), and hepatocellular carcinoma ( 34 ). However, the role of Zic5 is underexplored, probably because of its low expression and restricted expression pattern in tumors ( 9 – 11 ). Unexpectedly, we noted that the function of Zic2 was not dispensable, but rather, it may antagonize the function of Zic5 in glucose metabolism (Fig.…”

Zinc finger of the cerebellum 5 promotes colorectal cancer cell proliferation and cell cycle progression through enhanced CDK1/CDC25c signaling

“…Additionally, APC, P53, EGFR and VEGF were valuable for CRC prognosis [22][23][24]. Recent studies revealed that ZIC5 was a novel diagnostic marker of CRC [14]. However, ZIC5 function in CRC remained unclear.…”

“…Mechanistically, ZIC5 can increase the expression levels of genes which may be involved in the malignant proliferation of cancer cells, such as Wnt and cyclin D1. ZIC5 also promoted b-catenin to enter the nucleus of hepatocellular carcinoma (HCC) cells [11][12][13][14]. For example, Aruga et al reported that ZIC1/2/5 was highly expressed in meningiomas, and could be a diagnostic marker [11].…”

“…Later, ZIC5 was reported to be a promising marker of Gleason score 6 prostate cancer [ 13 ]. More recently, ZIC5 showed a critical role in CRC pathogenesis [ 14 ]. However, how ZIC5 regulated CRC malignancy remains unclear.…”