Golgi phosphoprotein 3 induces autophagy and epithelial–mesenchymal transition to promote metastasis in colon cancer

Abstract

In this study, we aimed to investigate whether and how Golgi phosphoprotein 3 (GOLPH3) facilitates colon cancer metastasis via the regulation of autophagy and epithelial–mesenchymal transition (EMT). The role GOLPH3 plays in colon cancer metastasis was analyzed using western blotting, immunohistochemistry, transwell, wound-healing, and zebrafish assays. Autophagy and EMT were assessed via RNA-sequencing (RNA-seq) analysis, mRFP-GFP-LC3 reporter assays, and their related markers. Significant associations were found between colon cancer clinical and pathological stages and poor prognosis. GOLPH3 facilitates colon cancer metastasis, both in vitro and in vivo. RNA-seq analysis of GOLPH3-overexpressing and control cell models revealed that GOLPH3 enhances EMT and autophagy. Moreover, examination of autophagic, epithelial, and mesenchymal markers in GOLPH3-overexpressing, -silenced, and control cell lines revealed that GOLPH3 promotes EMT and autophagy. When autophagy was inhibited, GOLPH3-promoted metastasis and EMT were counteracted in vitro and in vivo. Using RNA-seq, PI3K/Akt signaling was identified as the key downstream pathway on which GOLPH3 acts. Mechanistically, we demonstrated that GOLPH3 stimulates autophagy and induces EMT via the suppression of the phosphorylation of protein kinase B (Akt) at Ser473. In summary, GOLPH3 induces autophagy and EMT, promoting metastasis in colon cancer. Beyond this, and in contrast to conventional perspectives, we discovered that GOLPH3 represses the phosphorylation of Akt at Ser473.

Splicing factor SNRPA associated with microvascular invasion promotes hepatocellular carcinoma metastasis through activating NOTCH1/Snail pathway and is mediated by circSEC62/miR‐625‐5p axis

“…Mounting evidence has demonstrated that increased cancer cell invasion is associated with EMT-like process. [35][36][37][38] Interestingly, we found that overexpression of SNRPA promoted a transformation from the expression of epithelial markers to mesenchymal markers, indicating that SNRPA promoted the EMT-like process in HCC cells. Herein, we further explored the potential mechanism of SNRPA in the EMTlike process of HCC cells.…”

DHW-208, A Novel Phosphatidylinositol 3-Kinase (PI3K) Inhibitor, Has Anti-Hepatocellular Carcinoma Activity Through Promoting Apoptosis and Inhibiting Angiogenesis

“…Studies have shown that the PI3K pathway is involved in the migration, invasion and EMT of HCC cells ( 39 , 46 ). The effects of different concentrations of DHW-208 on the migration and invasion of Hep3B and Bel7402 cells were investigated.…”

GOLPH3 protein controls organ growth by interacting with TOR signaling proteins in Drosophila

“…In addition, because GOLPH3 is required to support Golgi apparatus integrity and the latter has been reported to inhibit autophagy [ 27 ] we expected induction of autophagy upon inactivation of dGOLPH3. While GOLPH3 has been recently involved in regulation of autophagy in human cultured cells and in a few tumor contexts [ 38 , 59 , 60 ], its role in the process is not understood. Our findings indicating that autophagy is supported by dGOLPH3 at the step of transcriptional induction of autophagy regulated by Mitf/TEB, suggest that loss of dGOLPH3 might inhibit translocation of TFEB from lysosomes to the nucleus.…”

“…We have previously demonstrated that the Drosophila GOLPH3 (dGOLPH3) protein, encoded by the sauron (sau) locus, accumulates at the cleavage site during telophase and acts as a key molecule during cytokinesis to couple PI(4)P signaling and membrane remodeling with actomyosin ring dynamics [ 35 – 37 ]. Frequent overexpression of GOLPH3 has been correlated with poor prognosis in multiple cancer types including breast cancer, colon cancer and glioblastoma [ 33 , 38 , 39 ]. The oncogenic activity of human GOLPH3 has been correlated with enhanced activity of growth factor-induced mTOR signaling [ 39 ].…”