title: BCLB, methylated in hepatocellular carcinoma, is a starvation stress sensor that induces apoptosis and autophagy through the AMPK-mTOR signaling cascade.
abstract: Epigenetic disruption of tumor suppressor genes (TSGs), particularly DNA methylation, plays a key role in hepatocellular carcinoma (HCC) pathogenesis. Through methylome study, we identified BCLB as a methylated gene in HCC. BCLB was methylated in all tumor cell lines with silenced or reduced expression. BCLB was further found to be silenced in 55.2% (58/105) of HCC samples, while 91.4% (96/105) of paired non-tumor tissues showed high BCLB expression. BCLB protein expression was significantly correlated with HBV status (p = 0.036), AFP (p = 0.048), tumor size (p = 0.006), and TNM stage (p = 0.022). The overall survival and disease-free survival rate of HCC patients with positive BCLB expression were both significantly higher than those with negative BCLB expression (p = 0.032 and 0.027, respectively). Ectopic expression of BCLB in HCC cells inhibited cell growth in vitro and in vivo. Mechanistic study showed that BCLB expression was a starvation stress sensor inducing apoptosis and autophagy simultaneously in HCC cells through the adenosine monophosphate-activated protein kinase AMPK-mTOR signaling cascade. Thus, epigenetic suppression of BCLB expression is involved in HCC development, which might have therapeutic implications for HCC patients.
authors.affiliation: Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Liu
authors.affiliation: Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Xiaotong
authors.initials: X
authors.lastname: Hu
authors.affiliation: Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Yeye
authors.initials: Y
authors.lastname: Kuang
authors.affiliation: Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Peijian
authors.initials: P
authors.lastname: Yan
authors.affiliation: Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Oncology in South China, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Lili
authors.initials: L
authors.lastname: Li
authors.affiliation: Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Oncology in South China, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Chen
authors.initials: C
authors.lastname: Li
authors.affiliation: Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Oncology in South China, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong. Electronic address: qtao@clo.cuhk.edu.hk.
authors.forename: Qian
authors.initials: Q
authors.lastname: Tao
authors.affiliation: Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. Electronic address: caixiujunzju@163.com.
authors.forename: Xiujun
authors.initials: X
authors.lastname: Cai
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000502:physiology*; D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D019175:DNA Methylation; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*
chemical_list: C117144:BCL2-like 10 protein; D019253:Proto-Oncogene Proteins c-bcl-2; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases
keywords: Apoptosis; Autophagy; BCLB; Methylation; Tumor suppressor gene