Fig. 8.

A working model explaining how SEC63 promotes metabolic reprogramming and epigenetic remodeling upon ER stress. Upon ER stress, SEC63 is phosphorylated at T537 by IRE1α. Phosphorylated SEC63 subsequently upregulates ACLY stability to produce more acetyl-CoA. Elevated acetyl-CoA is utilized for lipogenesis and histone acetylation for the transcription of UPR target genes. Meanwhile, SEC63 also enters into the nucleus together with ACLY. In the nucleus, SEC63 contributes to activation of UPR targets and induces Snail1 expression by increasing acetylation of SMAD3 to promote cancer cell metastasis. Upregulation of UPR targets and lipogenesis are beneficial for maintaining ER homeostasis to support cancer cell survival in response to stress. Metastasis is crucial for helping cancer cells seek new settlements upon microenvironmental stimuli. Abbreviations: ER, endoplasmic reticulum; HCC, hepatocellular carcinoma