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Correction for Zhou Et Al., Scaffold Association Factor B (SAFB) Is Required for Expression of Prenyltransferases and RAS Membra

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Correction for Zhou Et Al., Scaffold Association Factor B (SAFB) Is Required for Expression of Prenyltransferases and RAS Membra Correction CELL BIOLOGY Correction for “Scaffold association factor B (SAFB) is required for The authors note that Fig. 5 appeared incorrectly. Spe- expression of prenyltransferases and RAS membrane association,” cifically, in the middle panel of Fig. 5A, one of the bands by Mo Zhou, Leena Kuruvilla, Xiarong Shi, Stephen Viviano, was erroneously cropped out. The corrected figure and its Ian M. Ahearn, Caroline R. Amendola, Wenjuan Su, Sana Badri, legend appear below. The authors confirm that the correct James Mahaffey, Nicole Fehrenbacher, Jane Skok, Joseph image was derived from the same experiments as the other Schlessinger, Benjamin E. Turk, David A. Calderwood, and Mark images in the figure, and that the error does not affect R. Philips, which was first published November 30, 2020; 10.1073/ the interpretation of the data. The online version has been pnas.2005712117 (Proc. Natl. Acad. Sci. U.S.A. 117,31914–31922). corrected. A shNT shSAFB * B 60% - + - + FTI S P S P S P S P Total Ras 40% 100% ** RhoGDI 20% 50% CORRECTION CIMPR in cytosolic fraction FTI treated vs untreated vs untreated FTI treated percentage of total Ras percentage 0% 0% shNT shSAFB GTP-loaded Ras in A549 stables, shNT shSAFB C KRAS4B-dependent lung tumor KRAS4B-independent lung A549 H1437 %cell viability %cell viability FTI (log10, µM) dose response FTI (log10, µM) dose response H358 H1975 %cell viability %cell viability FTI (log10, µM) dose response FTI (log10, µM) dose response Fig. 5. Loss of SAFB diminishes membrane association and GTP loading of KRAS4B and sensitizes KRAS4B-dependent lung tumor cells to FTI treatment. KRAS4B-dependent (A549, H358) and KRAS4B-independent (H1437, H1975) lung tumor cells were stably transfected with a nontargeting shRNA or one targeting SAFB and plated untreated or treated with FTI (L-744,832). (A) A549 cells were disrupted by nitrogen cavitation, separated into S and P fractions by ultracentrifugation, and analyzed by immunoblots for the indicated proteins, including cytosolic (RhoGDI) and membrane (cation-independent manose-6- phosphate receptor; CIMPR) markers (Left). Bands were quantified by Li-Cor Odyssey and percent of total RAS in the cytosol is plotted to the Right; n = 3, *P < 0.05. (B) GTP loading of RAS in FTI-treated (25 μM L-744,832) A549 cells normalized to that measured in untreated cells with and without silencing SAFB by shRNA. **P < 0.01, n = 5. (C) The viability (normalized to untreated cells) of cells with and without stably silencing SAFB by shRNA was determined by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay after 6 d of treatment with indicated concentrations of FTI (L-744,832), n = 3. ns, not significant. Published under the PNAS license. Published July 14, 2021. www.pnas.org/cgi/doi/10.1073/pnas.2111162118 PNAS 2021 Vol. 118 No. 29 e2111162118 https://doi.org/10.1073/pnas.2111162118 | 1of1 Downloaded by guest on October 2, 2021 Scaffold association factor B (SAFB) is required for expression of prenyltransferases and RAS membrane association Mo Zhoua, Leena Kuruvillab, Xiarong Shib, Stephen Vivianob, Ian M. Ahearna, Caroline R. Amendolaa, Wenjuan Sua, Sana Badria, James Mahaffeya, Nicole Fehrenbachera, Jane Skoka, Joseph Schlessingerb, Benjamin E. Turkb, David A. Calderwoodb,c, and Mark R. Philipsa,1 aPerlmutter Cancer Center, NYU Langone Health, New York, NY 10016; bDepartment of Pharmacology, Yale School of Medicine, New Haven, CT 06510; and cDepartment of Cell Biology, Yale School of Medicine, New Haven, CT 06510 Edited by Douglas R. Lowy, National Cancer Institute, Bethesda, MD, and approved October 20, 2020 (received for review March 26, 2020) Inhibiting membrane association of RAS has long been considered drugs which led to the development of FTase inhibitors (FTIs) a rational approach to anticancer therapy, which led to the (1, 7). These agents lacked efficacy in KRAS-driven tumors be- development of farnesyltransferase inhibitors (FTIs). However, cause, although under physiologic conditions KRAS is a sub- FTIs proved ineffective against KRAS-driven tumors. To reveal al- strate for FTase and not GGTase I, when FTase is inhibited, ternative therapeutic strategies, we carried out a genome-wide KRAS becomes a substrate for GGTase I in a process referred to CRISPR-Cas9 screen designed to identify genes required for as alternative prenylation and thereby retains oncogenic function KRAS4B membrane association. We identified five enzymes in (8, 9). Thus, FTIs failed not because inhibiting KRAS mem- the prenylation pathway and SAFB, a nuclear protein with both brane association to block its function is a flawed idea but, DNA and RNA binding domains. Silencing SAFB led to marked rather, because FTIs were unable to block membrane associa- mislocalization of all RAS isoforms as well as RAP1A but not tion of KRAS. RAB7A, a pattern that phenocopied silencing FNTA, the prenyl- Although the posttranslational modifications of RAS HVRs transferase α subunit shared by farnesyltransferase and geranyl- required for membrane targeting are well characterized and geranyltransferase type I. We found that SAFB promoted RAS catalyzed by enzymes that are considered targets for anticancer membrane association by controlling FNTA expression. SAFB drug discovery, the current understanding of the full complexity knockdown decreased GTP loading of RAS, abrogated alternative of RAS trafficking continues to evolve (10–14), and it is likely prenylation, and sensitized RAS-mutant cells to growth inhibition that additional components yet to be appreciated contribute to by FTI. Our work establishes the prenylation pathway as para- the regulation of this pathway. Accordingly, there may be other mount in KRAS membrane association, reveals a regulator of pre- strategies for therapeutic intervention in RAS-driven cancers nyltransferase expression, and suggests that reduction in FNTA beyond inhibition of FTase. As a means to discover alternative expression may enhance the efficacy of FTIs. targets, we took an unbiased approach to identify genes required to target KRAS to cellular membranes or stabilize its membrane KRAS | RAS | prenyltransferase | farnesyltransferase | SAFB association. We identified a nuclear factor, SAFB, required for the expression of FNTA, the α subunit of both FTase and utations of RAS genes contribute to human cancer more Moften than those of any other oncogene, driving a quest for Significance therapeutic strategies that inhibit the function of oncogenic RAS (1). RAS proteins are small GTPases that operate as binary RAS oncogenes have long been a target for rational drug de- molecular switches to regulate pathways critical for cell prolif- sign. Whereas the recent advent of KRAS G12C inhibitors has eration and survival. RAS proteins can signal only when associ- offered hope for direct targeting of the oncoprotein, this mu- ated with cellular membranes (2, 3). Membrane association of tation occurs in only 11% of KRAS-driven tumors, and it re- RAS occurs by virtue of a series of critical posttranslational mains clear that multiple orthogonal approaches will be modifications (4). The four RAS proteins, HRAS, NRAS, required for definitive therapy. Inhibition of KRAS membrane KRAS4A, and KRAS4B, are ≥92% identical in their G domains association is an alternative, complementary approach. Here but differ substantially in a C-terminal hypervariable region we identify SAFB, a nuclear DNA/RNA binding protein, as a key (HVR). Whereas several modifications of the HVR that vary regulator of prenyltransferase expression. We show that si- among isoforms direct protein trafficking (5, 6), modification of a lencing SAFB reduces levels of FNTA, a subunit shared by two CaaX sequence (cysteine, aliphatic × 2, variable) at the C termi- prenyltransferases, and thereby sensitizes KRAS mutant cancer nus is universal and absolutely required for membrane association cells to growth inhibition with farnesyltransferase inhibitors (4). A large family of proteins, including RAS proteins and most (FTIs). Thus, reducing FNTA expression may be a strategy to of the >150 related small GTPases, terminate in a CaaX se- enhance the effectiveness of FTIs. quence. Nascent proteins that terminate in CaaX are substrates Author contributions: N.F., J. Skok, J. Schlessinger, B.E.T., D.A.C., and M.R.P. designed for a series of three modifications that include addition of a 15- or research; M.Z., L.K., X.S., S.V., I.M.A., C.R.A., W.S., S.B., and J.M. performed research; 20-carbon polyisoprene lipid to the cysteine (prenylation), endo- M.Z., L.K., X.S., I.M.A., C.R.A., W.S., S.B., J. Skok, B.E.T., D.A.C., and M.R.P. analyzed data; proteolysis of the aaX amino acids, and carboxylmethylation of and M.Z., I.M.A., C.R.A., W.S., B.E.T., D.A.C., and M.R.P. wrote the paper. the newly C-terminal prenylcysteine. These modifications are The authors declare no competing interest. catalyzed respectively by one of two prenyltransferases (farnesyl- This article is a PNAS Direct Submission. transferase [FTase] or geranylgeranyltransferase type 1 [GGTase Published under the PNAS license. I]), RAS-converting enzyme 1 (RCE1), and isoprenylcysteine 1To whom correspondence may be addressed. Email: [email protected]. carboxylmethyltransferase (ICMT). This article contains supporting information online at https://www.pnas.org/lookup/suppl/ Because RAS proteins require membrane association to doi:10.1073/pnas.2005712117/-/DCSupplemental. function, the prenylation pathway became a target for anti-RAS Published November 30, 2020. 31914–31922 | PNAS | December 15, 2020 | vol. 117 | no. 50 www.pnas.org/cgi/doi/10.1073/pnas.2005712117 GGTase I. Silencing SAFB abrogated alternative prenylation of KRAS4B away from the membrane and into the cytosol and KRAS and sensitized KRAS-driven tumor cells to FTIs, sug- nucleoplasm (Fig. 1C). Importantly, GFP-SAFB with silent PAM gesting that therapeutic strategies aimed at reducing FNTA ex- site mutations to make it insensitive to CRISPR rescued pression are worth pursuing.
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