(505.21) IGF2BP2 Promotes Cancer Progression by Degrading the RNA Transcript Encoding a v-ATPase Subunit

Poster Board Number: A285

Fangyu Wang (Cornell University), Arash Latifkar (Cornell University), James Mullmann (Cornell University), Elena Panizza (Cornell University), Irma Fernandez (Cornell University), Lu Ling (Cornell University), Andrew Miller (Cornell University), Claudia Fischbach (Cornell University), Robert Weiss (Cornell University), Hening Lin (Cornell University), Richard Cerione (Cornell University), Marc Antonyak (Cornell University)

IGF2BP2 binds to a number of RNA transcripts and has been suggested to function as a tumor promoter, although little is known regarding the mechanisms that regulate its roles in RNA metabolism. Here we demonstrate that IGF2BP2 binds to the 3’ untranslated region of the transcript encoding ATP6V1A, a catalytic subunit of the v-ATPase, and serves as a novel substrate for the NAD+-dependent deacetylase SIRT1, which regulates how IGF2BP2 affects the stability of the ATP6V1A transcript. When sufficient levels of SIRT1 are expressed, it catalyzes the deacetylation of IGF2BP2, which can bind to the ATP6V1A transcript but does not mediate its degradation. However, when SIRT1 expression is low, the acetylated form of IGF2BP2 accumulates, and upon binding to the ATP6V1A transcript, recruits the XRN2 nuclease which catalyzes transcript degradation. Thus, the stability of the ATP6V1A transcript is significantly compromised in breast cancer cells when SIRT1 expression is low or knocked-down. This leads to a reduction in the expression of functional v-ATPase complexes in cancer cells and to an impairment in their lysosomal activity, resulting in the production of a cellular secretome consisting of increased numbers of exosomes enriched in ubiquitinated protein cargo and soluble hydrolases including cathepsins, that together combine to promote tumor cell survival and invasiveness. These findings describe a previously unrecognized role for IGF2BP2 in mediating the degradation of an mRNA transcript essential for lysosomal function and highlight how its sirtuin-regulated acetylation state can have significant biological and disease consequences.

This research was supported by grants from NIH (lt;a href="https://www.sciencedirect.com/science/article/pii/S1534580719301881?via%3Dihub#gs1" style="color: blue;"gt;R35GM122575lt;/agt; and R01201402) to R.A.C., (U54CA210184) to C.F., (R01 CA223534) to R.A.C., H.L., and R.S.W., (lt;a href="https://www.sciencedirect.com/science/article/pii/S1534580719301881?via%3Dihub#gs1" style="color: blue;"gt;DK107868lt;/agt;) to H.L., (F30 CA25045) to J.J.M, grants from NIH (T32GM007273), a Cornell Deans Excellence Fellowship and a HHMI Gilliam Fellowship to I.R.F., and grants from NIH (lt;a href="https://www.sciencedirect.com/science/article/pii/S1534580719301881?via%3Dihub#gs1" style="color: blue;"gt;F99 CA234921lt;/agt;) and The Breast Cancer Coalition of Rochester to A.L. NTA was performed at the Cornell NanoScale Facility and was supported by NSF grant lt;a href="https://www.sciencedirect.com/science/article/pii/S1534580719301881?via%3Dihub#gs3" style="color: blue;"gt;NNCI-1542081lt;/agt;.



Diagram showing how SIRT1 influences ATP6V1A transcript stability to promote the production of a secretome, including exosomes and soluble hydrolases, that promotes invasiveness.