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Autophagy is a critical survival factor for cancer cells, whereby it maintains cellular homeostasis by degrading damaged organelles and unwanted proteins and supports cellular biosynthesis in response to stress. Cancer cells, including hepatocellular carcinoma (HCC), are often situated in a hypoxic, nutrient-deprived and stressful microenvironment where tumor cells are yet still able to adapt and survive. However, the mechanism underlying this adaptation and survival is not well-defined. We report deficiency of the post-translational modification enzyme protein arginine N-methyltransferase 6 (PRMT6) in HCC to promote the induction of autophagy under oxygen/nutrient-derived and sorafenib drug-induced stress conditions. Enhanced autophagic flux in HCC cells negatively correlated with PRMT6 expression, with the catalytic domain of PRMT6 critically important in mediating these autophagic activities. Mechanistically, PRMT6 physically interacts and methylates BAG5 to enhance the degradation of its interacting partner HSC70, a well-known autophagy player. The therapeutic potential of targeting BAG5 using genetic approach to reverse tumorigenicity and sorafenib resistance mediated by PRMT6 deficiency in HCC is also demonstrated in an in vivo model. The clinical implications of these findings are highlighted by the inverse correlative expressions of PRMT6 and HSC70 in HCC tissues. Collectively, deficiency of PRMT6 induces autophagy to promote tumorigenicity and cell survival in hostile microenvironments of HCC tumors by regulating BAG5-associated HSC70 stability through post-translational methylation of BAG5. Targeting BAG5 may therefore be an attractive strategy in HCC treatment by suppressing autophagy and inducing HCC cell sensitivity to sorafenib for treatment.

Oral squamous cell carcinoma (OSCC) is associated with a high potential of tumor recurrence and metastasis, leading to poor prognosis. Cell motility is an important factor in the progression and metastasis of cancers. Recently, Fascin has been linked to tumor progression by induction of cell motility. However, the precise roles of Fascin in OSCC have not been elucidated clearly. The aim of this study was to analyze the roles of Fascin in OSCC progression using OSCC clinical samples. We demonstrated that Fascin over-expression was found in OSCC clinical samples and its expression was significantly associated with nodal metastasis (p=0.027), tumor recurrence (p0.001) and poor patients' overall survival (p=0.013). Consistently, Fascin proteins were detected in all OSCC cell lines with the expression level corresponding to the invasion ability. To specifically investigate the mechanism of Fascin in OSCC, we examined the E-cadherin expression in the same set of OSCC specimens. Fascin was negatively correlated with E-cadherin expression (p=0.018, r=-0.513). In conclusion, our findings suggested that Fascin over-expression might enhance OSCC aggressiveness, possibly by interacting with E-cadherin expression.