hnRNP L regulates the tumorigenic capacity of lung cancer xenografts in mice via caspase-9 pre-mRNA processing.

Abstract

Caspase-9 is involved in the intrinsic apoptotic pathway and suggested to play a role as a tumor suppressor. Little is known about the mechanisms governing caspase-9 expression, but post-transcriptional pre-mRNA processing generates 2 splice variants from the caspase-9 gene, pro-apoptotic caspase-9a and anti-apoptotic caspase-9b. Here we demonstrate that the ratio of caspase-9 splice variants is dysregulated in non-small cell lung cancer (NSCLC) tumors. Mechanistic analysis revealed that an exonic splicing silencer (ESS) regulated caspase-9 pre-mRNA processing in NSCLC cells. Heterogeneous nuclear ribonucleoprotein L (hnRNP L) interacted with this ESS, and downregulation of hnRNP L expression induced an increase in the caspase-9a/9b ratio. Although expression of hnRNP L lowered the caspase-9a/9b ratio in NSCLC cells, expression of hnRNP L produced the opposite effect in non-transformed cells, suggesting a post-translational modification specific for NSCLC cells. Indeed, Ser52 was identified as a critical modification regulating the caspase-9a/9b ratio. Importantly, in a mouse xenograft model, downregulation of hnRNP L in NSCLC cells induced a complete loss of tumorigenic capacity that was due to the changes in caspase-9 pre-mRNA processing. This study therefore identifies a cancer-specific mechanism of hnRNP L phosphorylation and subsequent lowering of the caspase-9a/9b ratio, which is required for the tumorigenic capacity of NSCLC cells.

• Authors: Rachel Wilson Goehe, Jacqueline C Shultz, Charuta Murudkar, Sanja Usanovic, Nadia F Lamour, Davis H Massey, Lian Zhang, D Ross Camidge, Jerry W Shay, John D Minna, Charles E Chalfant
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 120 Issue 11 Pg. 3923-39 (Nov 2010) ISSN: 1558-8238 [Electronic] United States
• PMID: 20972334 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Heterogeneous-Nuclear Ribonucleoprotein L
• Isoenzymes
• RNA Precursors
• RNA, Small Interfering
• Caspase 9

Topics

• Alternative Splicing
• Animals
• Caspase 9 (genetics, metabolism)
• Cell Line, Tumor
• Exons
• Heterogeneous-Nuclear Ribonucleoprotein L (genetics, metabolism)
• Humans
• Isoenzymes (genetics, metabolism)
• Lung Neoplasms (enzymology, genetics, pathology)
• Male
• Mice
• Mice, SCID
• Neoplasm Transplantation
• RNA Precursors (genetics, metabolism)
• RNA, Small Interfering (genetics, metabolism)
• Silencer Elements, Transcriptional
• Transplantation, Heterologous