Role of HSPA1L as a cellular prion protein stabilizer in tumor progression via HIF-1α/GP78 axis

Abstract

The cellular prion protein (PrP) is associated with metastasis, tumor progression and recurrence; however, the precise mechanisms underlying its action is not well understood. Our study found that PrP degradation decreased tumor progression in colorectal cancer (CRC). In a CRC cell line and human CRC tissue exposed to hypoxia, induced heat-shock 70-kDa protein-1-like (HSPA1L) expression stabilized hypoxia-inducible factor-1α (HIF-1α) protein and promoted PrP accumulation and tumorigenicity in vivo. PrP was degraded via the proteasome pathway mediated by the ubiquitin-protein E3 ligase glycoprotein 78 (GP78), which interacts directly with PrP. However, hypoxia-induced HSPA1L interacted with GP78 and inhibited its functions. HSPA1L knockdown facilitated the interaction of GP78 and PrP, thereby increasing PrP ubiquitination. Thus, GP78 was identified as the ubiquitinase for PrP, thereby revealing an essential mechanism that controls PrP levels in CRC. Our results suggest that the HSPA1L/HIF-1α/GP78 axis has a crucial role in PrP accumulation during tumor progression.

Melatonin and 5‐fluorouracil co‐suppress colon cancer stem cells by regulating cellular prion protein‐Oct4 axis

“…Nevertheless, the correlation between PrP C and cancer stem cells remains to be determined. Our previous study has shown that high PrP C expression in colorectal cancer patients was significantly associated with metastasis risk, advanced clinical stages, and patient survival . We identified the correlation between PrP C and colon cancer stem cells by confirming the association between PrP C and Oct4.…”

“…PrP C and HSP70‐HSP90‐organizing protein are associated with glioblastoma proliferation and low patient survival rates . Our previous study has shown that HSPA1L stabilizes cellular prion protein . PRNP overexpression increased HSPA1L expression.…”

Melatonin suppresses senescence‐derived mitochondrial dysfunction in mesenchymal stem cells via the HSPA1L–mitophagy pathway

“…This study has verified that melatonin-induced mitophagy in Lee, Han, Yoon, et al, 2017;Lee et al, 2018;Mayer & Bukau, 2005;Wang et al, 2013). In damaged mitochondria of HeLa cells, HSPA1L and BAG family molecular chaperone regulator 4 induces the translocation of parkin to mitochondria, leading to mitochondrial quality control (Hasson et al, 2013).…”

“…This study has verified that melatonin‐induced mitophagy in senescent MSCs is regulated by the recruitment of the HSPA1L‐PrP C complex. HSPA1L contributes to protein stabilization, cell growth, apoptosis, and signal transduction (Hasson et al, ; Lee, Han, Yoon, et al, ; Lee et al, ; Mayer & Bukau, ; Wang et al, ). In damaged mitochondria of HeLa cells, HSPA1L and BAG family molecular chaperone regulator 4 induces the translocation of parkin to mitochondria, leading to mitochondrial quality control (Hasson et al, ).…”

Melatonin‐stimulated exosomes enhance the regenerative potential of chronic kidney disease‐derived mesenchymal stem/stromal cells via cellular prion proteins

“…To further investigate how miR‐4516 regulates the expression of PrP C , the level of GP78 was assessed via expression of miR‐4516. Our previous study has shown that the level of PrP C is regulated by GP78 which is an membrane‐anchored E3 ligase . Inhibition of miR‐4516 significantly increased the expression of GP78, resulting in augmentation of ubiquitination of PrP C (Figure A‐D).…”