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Background and Aims  Hepatitis B virus (HBV) integrations are common in hepatocellular carcinoma (HCC). In particular, alterations of the telomerase reverse transcriptase ( TERT ) gene by HBV integrations are frequent; however, the molecular mechanism and functional consequence underlying  TERT  HBV integration are unclear.    Approach and Results  We adopted a targeted sequencing strategy to survey HBV integrations in human HBV‐associated HCCs (n = 95). HBV integration at the  TERT  promoter was frequent (35.8%, n = 34/95) in HCC tumors and was associated with increased  TERT  mRNA expression and more aggressive tumor behavior. To investigate the functional importance of various integrated HBV components, we employed different luciferase reporter constructs and found that HBV enhancer I (EnhI) was the key viral component leading to  TERT  activation on integration at the  TERT  promoter. In addition, the orientation of the HBV integration at the  TERT  promoter further modulated the degree of  TERT  transcription activation in HCC cell lines and patients’ HCCs. Furthermore, we performed array‐based small interfering RNA library functional screening to interrogate the potential major transcription factors that physically interacted with HBV and investigated the cis‐activation of host  TERT  gene transcription on viral integration. We identified a molecular mechanism of  TERT  activation through the E74 like ETS transcription factor 4 (ELF4), which normally could drive HBV gene transcription. ELF4 bound to the chimeric HBV EnhI at the  TERT  promoter, resulting in telomerase activation. Stable knockdown of ELF4 significantly reduced the  TERT  expression and sphere‐forming ability in HCC cells.    Conclusions  Our results reveal a cis‐activating mechanism harnessing host ELF4 and HBV integrated at the  TERT  promoter and uncover how  TERT  HBV‐integrated HCCs may achieve  TERT  activation in hepatocarcinogenesis.

hepatology

Hepatitis B Virus–Telomerase Reverse Transcriptase Promoter Integration Harnesses Host ELF4, Resulting in Telomerase Reverse Transcriptase Gene Transcription in Hepatocellular Carcinoma