HBP21, a chaperone of heat shock protein 70, functions as a tumor suppressor in hepatocellular carcinoma

Inactivation of tumor suppressor genes, caused by genetic and epigenetic alterations, is one of the key issues in the development and progression of cancer. To identify and characterize cancer related genes in hepatocellular carcinoma (HCC) pathogenesis, transcriptome sequencing has been applied to compare expression profiles between tumor and non-tumor tissues. Among the down-regulated genes, heat shock binding protein 21 (HBP21) was selected for further study. In this study, down-regulation of HBP21 was frequently detected in primary HCCs (87/120, 72.5%), which was significantly associated with advanced clinical stage (P = 0.049), poor differentiation (P = 0.018) and poor prognosis (P = 0.026). Further study found that down-regulation of HBP21 in HCC was mainly caused by allele loss and promoter methylation. Functional study found that HBP21 could inhibit tumor cell growth rate, foci formation and colony formation in soft agar, and tumor formation in nude mice when it was transfected into HCC cells. Molecular study found that HBP21 could promote cell apoptosis, especially under adverse conditions such as heat and chemotherapeutic agent treatment. As a chaperone of heat shock protein 70 (HSP70), HBP21 could inhibit interaction between HSP70 and Bax, increased Bax protein translocation from cytoplasm to mitochondria, and subsequently increased the release of cytochrome c into cytoplasm, and finally induced apoptosis. Clinically, HBP21 could be used as a prognostic biomarker for HCC outcome prediction and might be also as a novel therapeutic agent in HCC treatment.