Transcription co-activator P300 activates Elk1-aPKC-ι signaling mediated epithelial-to-mesenchymal transition and malignancy in hepatocellular carcinoma

Abstract

Epithelial-to-mesenchymal transition (EMT) plays an important role in invasion and metastasis of hepatocellular carcinoma (HCC). Our previous study found that atypical protein kinase C-ι (aPKC-ι) promoted the EMT process in HCC. However, how the aPKC-ι signaling pathway is regulated in HCC has not been elucidated. In this study, vector transfection was utilized to study the invasion of HCC cells, and the mechanism between P300 and aPKC-ι signaling pathways in regulating the EMT process of HCC was further elucidated in vitro and in vivo. We found both P300 and aPKC-ι were highly expressed in HCC and they were correlated with tumor progression and poor survival in HCC patients. P300 knockdown inhibited EMT, invasion and other malignant events of HCC cells but promoted cell apoptosis and cycle arrest. However, the effects mediated by P300 knockdown were abolished by aPKC-ι overexpression. Further studies showed that P300 upregulates aPKC-ι expression through increasing the transcription of Elk1, a transcriptional activator of aPKC-ι, and stabilizing Elk1 protein and its phosphorylation. In conclusion, our work uncovered the molecular mechanism by which oncogenic aPKC-ι is upregulated in HCC and suggests that P300, like aPKC-ι, may be used as a prognostic biomarker and therapeutic target in patients with HCC.

Bromodomain-containing protein 9 promotes the growth and metastasis of human hepatocellular carcinoma by activating the TUFT1/AKT pathway

“…Our previous study demonstrated that P300 was able to affect the H3K27Ac of various cancer-related genes 17 , 24 . P300 was confirmed to be overexpressed in HCC and promoted the progression of HCC 34 – 36 . The ChIP assay for P300 in our study demonstrated that the engagement of P300 in the TUFT1 promoter region was increased after BRD9 overexpression.…”

P300-dependent acetylation of histone H3 is required for EGFR-mediated HMGA2 transcription in hepatocellular carcinoma

“…Numerous studies have demonstrated p300 was associated with enhanced EMT and correlates with poor prognosis in these cancers [41,43]. Overexpression of p300 promotes cell proliferation, migration, and invasion in NSCLC cells [42]; knockdown of p300 inhibited EMT, invasion and other malignant events of HCC cells [43]. However, we must note that p300 may act as a suppressor of tumor metastasis in some cancers.…”

“…Abnormal expression of p300 has been identi ed in esophageal squamous carcinoma, NSCLC cells and hepatocellular carcinoma [41][42][43]. Numerous studies have demonstrated p300 was associated with enhanced EMT and correlates with poor prognosis in these cancers [41,43].…”

“…Abnormal expression of p300 has been identi ed in esophageal squamous carcinoma, NSCLC cells and hepatocellular carcinoma [41][42][43]. Numerous studies have demonstrated p300 was associated with enhanced EMT and correlates with poor prognosis in these cancers [41,43]. Overexpression of p300 promotes cell proliferation, migration, and invasion in NSCLC cells [42]; knockdown of p300 inhibited EMT, invasion and other malignant events of HCC cells [43].…”

The E-Twenty-Six Family in Hepatocellular Carcinoma: Moving into the Spotlight

“…ELF3 represses E-cadherin and promotes EMT in HCC cells via suppressing miR-141-3p, thereby activating ZEB1 ( 38 ). ELK1 promotes invasion and EMT in HCC cells via upregulating aPKC-ι expression ( 66 ). Knocking down ETV4 completely blocks the facilitation of cell invasion and migration mediated by CIC deficiency ( 67 ).…”