Wotton Lab

The overall interest of the lab is in the control of tumor progression by changes in signaling and transcriptional regulators. Our original focus was on transforming growth factor beta (TGF beta) signaling, and the role of two transcriptional repressors (TGIF1 and TGIF2) that can limit the response to TGF beta signaling. Much of our older work focused on the regulation of gene expression by the TGIF transcriptional repressors, and addressed the role of TGIFs in normal mammalian development. In addition to their roles in TGF beta signaling, TGIFs can repress transcription when bound directly to DNA. This TGIF function is independent of TGF beta signaling, and the SMAD transcription factors that mediate the TGF beta response.

More recently we have examined a potential role for TGIFs in colon cancer, where we found increased expression of both proteins in tumors compared to normal tissue. Using mouse models, we demonstrated that increased TGIF expression promotes colon tumor growth. Transcriptional profiling identified several metabolic pathways as being the primary gene expression programs that were deregulated in TGIF mutant colon tumors. These changes were independent of TGF beta signaling, and we found direct TGIF recruitment to the proximal promoters of several of these metabolic genes.

The majority of our current work focuses on the control of colon cancer development and progression by metabolism, and the effects of metabolic pathways on chromatin and transcriptional regulation. Colon tumors develop in an unusual metabolic environment, where gut bacteria generate high levels of short chain fatty acids (SCFA), including acetate and butyrate that are metabolized by normal colon epithelial cells. Despite this, early colon tumors reprogram their metabolism to become more dependent on glycolysis. We are currently testing whether this switch to glycolysis requires the downregulation of SCFA metabolic pathways, and whether higher SCFA metabolic pathway activity limits tumor development.

A number of SCFA metabolic enzymes, including some involved in acetate and butyrate metabolism, are downregulated in colon cancer, which may create tumor specific vulnerabilities that could be targeted therapeutically. Conversion of acetate to acetyl CoA provides a substrate for lipid synthesis and for histone acetylation, and we are currently examining whether targeting both acetyl CoA synthesis and its use for histone modification is an effective approach to limiting tumor growth. We are using both RNA-seq and ATAC-seq to identify genes and regulatory regions that are affected by these pathways, and to identify additional gene expression programs that could be targeted together with acetyl CoA synthesis and use.

Although our focus on these metabolic pathways was initially driven by the unique metabolic environment in the colon, we have begun to expand these approaches to other tumor types. Initial results suggest that targeting at least some of these metabolic pathways might also be effective in other cancers.

Yang, C., Wierbiłowicz, K., Dworak, N.M., Bae, S.Y., Tengse, S.B., Abianeh, N., Drake, J.M., Abbas, T., Ratan, A., Wotton, D., and Paschal, B.M. (2023). Induction of PARP7 Creates a Vulnerability for Growth Inhibition by RBN2397 in Prostate Cancer Cells. Cancer Res. Commun. 3(4), 592-606. PMID: 37077937

Yang, C., Jividen, K., Dworak, N., Oostdyk, L., Remlein, B., Pourfarjam, Y., Kim, I., Du, K., Abbas, T., Sherman, N.E., Wotton, D. and Paschal, B.M. (2021). Androgen signaling uses a writer and a reader of ADP-ribosylation to regulate protein complex assembly. Nat. Commun. 12(1), 2705. PMID: 33976187

Kamata, T., Yang, C., Melhuish, T.A., Frierson, H.F., Wotton, D. and Paschal, B.M. (2021). Post-transcriptional regulation of PARP7 protein stability is
controlled by androgen signaling. Cells. 10(2), 363. PMID: 33572475

Saha, S., Kiran, M., Kuscu, C., Chatrath, A., Wotton, D., Mayo, M.W. and Dutta, A. (2020). A tumor suppressive long noncoding RNA DRAIC interacts with IKK and inhibits NF-κB. Cancer Research. 80, 950-963. PMID: 31900260

Shah, A., Melhuish, T.A., Fox, T.E., Frierson, H.F. and Wotton, D. (2019). TGIF transcription factors repress acetyl CoA metabolic gene expression and promote intestinal tumor growth. Genes & Dev. 33, 388-402. PMID: 30808659

Melhuish, T.A., Kowalczyk, I., Manukyan, A., Zhang, Y., Shah, A., Abounader, R. and Wotton, D. (2018). Myt1 and Myt1l transcription factors limit proliferation in GBM cells by repressing YAP1 expression. Biochim Biophys Acta Gene Regul Mech. 1861, 983-995. PMID: 30312684

Wotton, D. and Taniguchi, K. (2018). Functions of TGIF Homeodomain Proteins and Their Roles in Normal Brain Development and Holoprosencephaly. Am. J. Med. Genet. 178C, 128-139. PMID: 29749689

Parini, P., Melhuish, T.A., Wotton, D., Larsson, L., Ahmed, O., Eriksson, M. and Pramfalk, C. (2018). Overexpression of transforming growth factor β induced factor homeobox 1 represses NPC1L1 and lowers markers of intestinal cholesterol absorption. Atheroscleorsis. 275, 246-255. PMID: 29980051

Hao, Y., Bjerke, G.A., Pietrzak, K., Melhuish, T.A., Han, Y., Turner, S.D., Frierson, H.F. and Wotton, D. (2018). TGFβ Signaling Limits Lineage Plasticity in Prostate Cancer. PLoS Gen. 14(5):e1007409. doi: 10.1371/journal.pgen.1007409. PMID: 29782499

Carlton, A.L., Illendula, A., Gao, Y., Llaneza, D.C., Boulton, A., Shah, A., Rajewski, R.A., Landen, C.N., Wotton, D. and Bushweller, J.H. (2018). Small molecule inhibition of the CBFβ/RUNX interaction decreases ovarian cancer growth and migration through alterations in genes related to epithelial-to-mesenchymal transition. Gynecol. Oncol. 149(2), 350-360. PMID: 29551565

Manukyan, A., Kowalczyk, I., Melhuish, T.A., Lemiesz, A. and Wotton, D. (2018). Analysis of transcriptional activity by the Myt1 and Myt1l transcription factors. J. Cell. Biochem. 119(6), 4644-4655. PMID: 29291346

Wotton, D., Pemberton, L.F. and Merrill, J.C. (2017). SUMO and chromatin remodelling. In: SUMO Regulation of Cellular Processes, 2nd edition. Editor: Wilson, V.G. Adv Exp Med Biol. 2017;963:35-50. PMID: 28197905

Yang, C., Melhuish, T.A., Spencer, A., Ni, L., Hao, Y., Jividen, K., Harris, T., Snow, C., Frierson, H.F., Wotton, D. and Paschal, B.M. (2017). The Protein Kinase C Super-family Member PKN is Regulated by mTOR and Influences Differentiation During Prostate Cancer Progression. The Prostate. 77, 1452-1467. doi: 10.1002/pros.23400. PMID: 28875501

Anderson, A.E., Taniguchi, K., Hao, Y., Melhuish, T.A., Shah, A., Turner, S.D., Sutherland, A.E. and Wotton, D. (2017). Tgif1 and Tgif2 repress expression of the RabGAP, Evi5l. Mol. Cell. Biol. 37(5), pii: e00527-16. DOI: 10.1128/MCB.00527-16. PMID: 27956704

Taniguchi, K., Anderson, A.E., Melhuish, T.A., Carlton, A.L. Manukyan, A., Sutherland, A.E. and Wotton, D. (2017). Genetic and Molecular Analyses indicate independent effects of TGIFs on Nodal and Gli3 in neural tube patterning. Eur. J. Human Gen. 25, 208-215. PMID: 27924807

Melhuish, T.A., Taniguchi, K. and Wotton, D. (2016). Tgif1 and Tgif2 regulate axial patterning in mouse. PLoS ONE. 2016 May 17;11(5):e0155837. PMID: 27187787

Bjerke, G.A., Pietrzak, K., Melhuish, T.A., Frierson, H.F., Paschal, B.M. and Wotton, D. (2014). Prostate Cancer Induced by Loss of Apc is restrained by TGF signaling. PLoS ONE. 9(3): e92800. PMID: 24651496

Pramfalk, C., Melhuish, T.A., Wotton, D. Jiang, Z-Y., Eriksson, M. and Parini, P. (2014). TG interacting factor 1 acts as a transcriptional repressor of sterol O-acyltransferase 2. J. Lipid Res. 55, 709-717. PMID: 24478032

Yan, L., Womack, B., Wotton, D., Guo, Y., Shyr, Y., Dave, U., Li, C., Hiebert, S., Brandt, S. and Hamid, R. (2013). Tgif1 regulates the quiescence and self-renewal of hematopoietic stem cells. Mol. Cell. Biol. 33, 4824-4833. PMID: 24100014

Bjerke, G.A., Yang, C., Frierson, H.F., Paschal, B.M. and Wotton, D. (2013). Activation of Akt Signaling in Prostate Induces a TGF Mediated Restraint on Cancer Progression and Metastasis. Oncogene. 2013 Sep 2. doi: 10.1038/onc.2013.342. PMID: 23995785