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PTEN antagonises Tcl1/hnRNPK-mediated G6PD pre-mRNA splicing which contributes to hepatocarcinogenesis
  1. Xuehui Hong1,
  2. Ruipeng Song1,
  3. Huiwen Song2,
  4. Tongsen Zheng1,
  5. Jiabei Wang1,
  6. Yingjian Liang1,
  7. Shuyi Qi3,
  8. Zhaoyang Lu1,
  9. Xuan Song1,
  10. Hongchi Jiang1,
  11. Lianxin Liu1,
  12. Zhiyong Zhang4
  1. 1Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
  2. 2Department of Cardiovascular Medicine and Department of Emergence, Baoan Hospital, Southern Medical University, ShenZhen, China
  3. 3Department of Gerontology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
  4. 4Department of Surgery, Robert-Wood-Johnson Medical School University Hospital, University of Medicine & Dentistry of New Jersey, New Brunswick, New Jersey, USA
  1. Correspondence to Dr Zhiyong Zhang, Department of Surgery, Robert-Wood-Johnson Medical School University Hospital, Rutgers University, 125 Paterson Street, New Brunswick, NJ 08901, USA; zhiyongzhng3{at}gmail.com Dr Lianxin Liu, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, #23 Youzheng Street, Harbin, Heilongjiang Province, 150001, China; liulx{at}ems.hrbmu.edu.cn Dr Hongchi Jiang, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, #23 Youzheng Street, Harbin, Heilongjiang Province, 150001, China; jianghongchi01{at}163.com

Abstract

Background Mounting epidemiological evidence supports a role for phosphatase and tensin homologue (PTEN)-T cell leukaemia 1 (Tcl1) signalling deregulation in hepatocarcinogenesis.

Objective To determine the molecular and biochemical mechanisms by which the PTEN/Tcl1 axis regulates the pentose phosphate pathway (PPP) in hepatocellular carcinoma (HCC).

Methods We compared levels of PTEN and glucose-6-phosphate dehydrogenase (G6PD) mRNA in human HCC and healthy liver tissue. We measured PPP flux, glucose consumption, lactate production, nicotinamide adenine dinucleotide phosphate (NADPH) levels and lipid accumulation. We investigated the PTEN/Tcl1 axis using molecular biology, biochemistry and mass spectrometry analysis. We assessed proliferation, apoptosis and senescence in cultured cells, and tumour formation in mice.

Results We showed that PTEN inhibited the PPP pathway in human liver tumours. Through the PPP, PTEN suppressed glucose consumption and biosynthesis. Mechanistically, the PTEN protein bound to G6PD, the first and rate-limiting enzyme of the PPP and prevented the formation of the active G6PD dimer. Tcl1, a coactivator for Akt, reversed the effects of PTEN on biosynthesis. Tcl1 promoted G6PD activity and also increased G6PD pre-mRNA splicing and protein expression in a heterogeneous nuclear ribonucleoprotein (hnRNPK)-dependent manner. PTEN also formed a complex with hnRNPK, which inhibited G6PD pre-mRNA splicing. Moreover, PTEN inactivated Tcl1 via glycogen synthase kinase-3β (GSK3β)-mediated phosphorylation. Importantly, Tcl1 knockdown enhanced the sensitivity of HCC to sorafenib, whereas G6PD knockdown inhibited hepatocarcinogenesis.

Conclusions These results establish the counteraction between PTEN and Tcl1 as a key mechanism that regulates the PPP and suggest that targeting the PTEN/Tcl1/hnRNPK/G6PD axis could open up possibilities for therapeutic intervention and improve the prognosis of patients with HCC.

  • LIVER METABOLISM
  • HEPATOCELLULAR CARCINOMA
  • MOLECULAR MECHANISMS
  • MOLECULAR BIOLOGY
  • GLUCOSE METABOLISM

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