Abstract
mTORC1-dependent SRPK2 phosphorylation induces splicing of lipogenic transcripts involved in tumor growth.
Major finding: mTORC1-dependent SRPK2 phosphorylation induces splicing of lipogenic transcripts involved in tumor growth.
Mechanism: SRPK2 activates SR proteins and the splicing factor U1-70K to prevent intron retention.
Impact: SRPK2 may be a potential therapeutic target to block lipogenesis and suppress mTORC1-driven tumors.
mTORC1 is a master regulator of cellular anabolic processes and is frequently hyperactivated in cancer to promote cell growth and survival. Identification of downstream mTORC1 targets might facilitate therapeutic targeting of mTORC1 signaling. Lee and colleagues identified the SR protein kinase SRPK2 as a downstream target of mTORC1 signaling that is phosphorylated at Ser494 and Ser497 in an mTORC1-dependent manner. SRPK2 was directly phosphorylated at Ser494 by S6K1 downstream of mTORC1 signaling, and this allowed for phosphorylation of Ser497 by CK1. Phosphorylation of SRPK2 facilitated its transport into the nucleus where it phosphorylated SR target proteins. mTORC1 inhibition or SRPK2 depletion reduced expression of enzymes required for de novo lipid synthesis, including ACLY, ACSS2, HMGCS1, MVD, FDFT1, FASN, and SCD1. However, the reduced mRNA and protein levels occurred despite increased promoter activity, suggesting post-transcriptional mechanisms of regulation. Indeed, SRPK2 enhanced the mRNA stability of these lipogenic genes by promoting efficient intron splicing. Mechanistically, SRPK2 activated SR proteins and promoted their binding to the splicing factor U1-70K to induce splicing of lipogenic pre-mRNAs for de novo synthesis of fatty acids and cholesterol. Depletion of SRPK2 resulted in intron retention in lipogenic genes, resulting in nonsense-mediated mRNA decay. An SRPK1/2 inhibitor decreased expression of lipogenic enzymes, reduced de novo synthesis of fatty acids, and suppressed the growth of tumor cells expressing high levels of mTORC1. In vivo, SRPK2 inhibition suppressed tumor growth in xenografts of multiple cancer cell lines expressing high levels of mTORC1. Altogether, these finding indicate that SRPK2 is an essential downstream mediator of mTORC1-dependent lipogenesis and may be a therapeutic target in mTORC1-driven tumors.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.
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