Directory

Research Interests:
Several small GTPases, including RAS proteins, are functionally modified by the posttranslational modification process of prenylation and post-prenylation methylation.  The last step of this modification pathway is catalyzed by a unique enzyme termed isoprenylcysteine carboxylmethyltransferase (ICMT). Genetic and pharmacological evidence supports the importance of ICMT modification of its substrates in oncogenesis and tumor progression. Hence, inhibition of ICMT is a potential approach in the development of novel cancer therapeutics.  We are working to: (1) delineate the mechanisms through which ICMT substrate(s) contribute to tumorigenesis and tumor progression, and (2) develop novel ICMT inhibitors for preclinical and clinical development.
 
My research program is focusing on:
The role of ICMT in tumorigenesis and drug resistance 
In recent years, we have found that suppression of ICMT function induces cancer cell metabolic disarray, autophagy, cell cycle arrest and ultimately cell death. To study the impact of ICMT inhibition in RAS-driven human cancers, we created ICMT knocked-out isogenic cancer cells in both a RAS transformation model system and in naturally occurring human cancer cells. The ICMT-null cells lost the potential to be transformed by all isoforms of mutant RAS, demonstrating the importance of ICMT function in malignant transformation and tumor maintenance. In recent studies we found that inhibition of ICMT abolished the “stemness” of select human cancers, and showed synergistic reduction of in vivo tumor growth with cytotoxic therapeutics. We are working to identify the substrate(s) and delineate the signaling mechanisms responsible for ICMT-dependent tumorigenesis. 

The role of ICMT in promoting cancer metastasis by regulating cell polarity, migration, invasion and tumor microenvironment 
Prior studies have suggested that suppression of ICMT function leads to impaired cancer cell attachment and movement.  Among the ICMT substrates, Rho family of GTPases is among the most well-known regulators of cell morphology and movement. Our ongoing work has not only confirmed the importance of RHO family members, but also identified specific RAB GTPase substrates of ICMT such as RAB4, as important regulators of cell polarity and migration. Additionally, in vivo models have substantiated the critical role of ICMT in supporting the process of cancer cell metastasis; with evidence pointing to ICMT involvement in both cell migration and microenvironment modulation. We continue to study the molecular mechanisms at both the in vitro and the in vivo levels. 

Potential application of ICMT inhibitors as cancer therapeutics
The evidence of the importance of ICMT in regulatory biology of cancer supports the potential of ICMT inhibitors as cancer therapeutics. We have an ongoing program to discover and evaluate ICMT inhibitors.

Selected Reference:

RAB4A GTPase regulates epithelial-to-mesenchymal transition by modulating RAC1 activation.
Subbulakshmi Karthikeyan, Patrick J Casey, Mei Wang. (2022)
Breast Cancer Research. 24(1):72. doi: 10.1186/s13058-022-01564-6.

Suppression of isoprenylcysteine carboxylmethyltransferase compromises DNA damage repair.
Tang J, Casey PJ, Wang M (2021)
Life Sci Alliance. doi:10.26508/lsa.202101144.  PMID: 34610973

Isoprenylcysteine carboxylmethyltransferase is required for the impact of mutant KRAS on TAZ protein level and cancer cell self-renewal. 
Chai TF, Manu KA, Casey PJ and Wang M (2020)
Oncogene. Doi:10.1038/s41388-020-1364-7. Online ahead of print. PMID: 32561852

Targeting Aberrant RAS/RAF/MEK/ERK Signaling for Cancer Therapy. 
Degirmenci U, Wang M and Hu J (2020)
Cells. 9(1) pii: E198. doi: 10.3390/cells9010198. PMID: 31941155

G alpha-13 induces C-X-C motif chemokine ligand 5 expression in prostate cancer cells by transactivating NF-κB.
Lim WK, Chai X, Ghosh S, Ray D, Wang M, Rasheed SAK and Casey PJ (2019) 
J Biol Chem. 294(48):18192-18206. doi: 10.1074/jbc RA119.010018. PMID: 31636124

Evaluating the Epithelial-Mesenchymal Program in Human Breast Epithelial Cells Cultured in Soft Agar Using a Novel Macromolecule Extraction Protocol.
Lau HY, Tang J, Casey PJ, Wang M (2021)
Cancers.Feb 15;13(4):807.  PMID: 33671920

Protein prenylation: unique fats make their mark on biology. 
Wang M* and Casey PJ* (2016) 
Nat Rev Mol Cell Biol. 17:110-122. PMID: 26790532

Small change, big effect: Taking RAS by the tail through suppression of post-prenylation carboxylmethylation.
Lau HY and Wang M (2018)
Small GTPases. Jan 25:1-9. PMID: 29261009

Isoprenylcysteine carboxylmethyltransferase function is essential for RAB4A-mediated integrin β3 recycling, cell migration and cancer metastasis.
Do MT, Chai TF, Casey PJ and Wang M (2017)
Oncogene. 36(41):5757-5767. PMID: 28604748

Inhibition of Isoprenylcysteine carboxylmethyltransferase induces cell cycle arrest and apoptosis through p21 and p21-regulated BNIP3 induction in pancreatic cancer.
Manu KA, Chai TF, Teh JT, Zhu WL, Casey PJ and Wang M (2017)
Mol Cancer Ther. 16(5):914-923. PMID: 28167504

Isoprenylcysteine carboxylmethyltransferase is critical for malignant transformation and tumor maintenance by all RAS isoforms.
Lau HY, Tang J, Casey PJ, and Wang M (2017)
Oncogene. 36(27):3934-3942. PMID: 28192404

Adipocyte ceramides regulate subcutaneous adipose browning, inflammation, and metabolism. 
Chaurasia B, Kaddai VA, Lancaster GI, Henstridge DC, Sriram S, Galam DL, Gopalan V, Prakash KN, Velan SS, Bulchand S, Tsong TJ, Wang M, Siddique MM, Yuguang G, Sigmundsson K, Mellet NA, Weir JM, Meikle PJ, Bin M Yassin MS, Shabbir A, Shayman JA, Hirabayashi Y, Shiow ST, Sugii S, Summers SA (2016)
Cell Metab. 24(6):820-834.  PMID: 27818258

Activation of MAPK/ERK signaling by Burkholderia pseudomallei cycle inhibiting factor (Cif).
Ng MY, Wang M, Casey PJ, Gan YH and Hagen T (2017)
Plos One. 12(2):e0171464. doi: 10.1371/journal.pone.0171464. PMID: 28166272

Inhibition of isoprenylcysteine carboxylmethyltransferase augments BCR-ABL1 tyrosine kinase inhibition-induced apoptosis in chronic myeloid leukaemia. 
Sun WT, Xiang W, Ng BL, Asari K, Bunte RM, Casey PJ, Wang M* and Chua C* (2015) 
Exp Hemato. 44:189-192. PMID: 26706195

Isoprenylcysteine carboxylmethyltransferase regulates mitochondrial respiration and cancer cell metabolism. 
Teh JT, Zhu WL, Ilkayeva OR, Li Y, Gooding J, Casey PJ, Summers SA, Newgard CB, Wang M (2014) 
Oncogene. 34:3296-304. PMID: 25151967

Forkhead box protein O3 transcription factor negatively regulates autophagy in human cancer cells by inhibiting forkhead box protein O1 expression and cytosolic accumulation.
Zhu WL, Tong H, Teh JT, and Wang M (2014)
PLoS One. 9(12):e115087. PMID: 25546383

An Improved Isoprenylcysteine Carboxymethyltransferase Inhibitor Induces Cancer Cell Death and Attenuates Tumor Growth in vivo. 
Lau HY, Ramanujulu PM, Guo DY, Wirawan M, Casey PJ, Go ML and Wang M (2014)
Cancer Biol Ther. 15(9):1280-91. PMID: 24971579

Functionalized indoleamines as potent, drug-like inhibitors of isoprenylcysteine carboxylmethyltransferase (Icmt).
Ramanujulu PM, Yang T, Yap SQ, Wong FC, Casey PJ, Wang M, Go ML (2013). 
Euro J Med Chem. 63: 378-386. PMID: 23514631

Cysmethynil, a specific small molecule inhibitor of isoprenylcysteine carboxylmethyl transferase.
Wang M (2011) 
Protein Prenylation, Part B, The Enzymes 27th Edition.

A role for Rac3 GTPase in the regulation of autophagy.
Zhu W, Hossain MS, Guo DY, Sen L, Tong H, Khakpoor A, Casey PJ, Wang M (2011) 
J Biol Chem. 2011; 286:35291-8. PMID: 28152230

Amino derivatives of indole as potent inhibitors of isoprenylcysteine carboxyl methyltransferase.
Go ML, Leow JL, Gorla SK, Schueller A, Wang M, Casey PJ (2010) 
J Med Chem. 53:6838-50. PMID: 20809634

Inhibition of Isoprenylcysteine Carboxyl methyltransferase Induces Autophagic-Dependent Apoptosis and Impairs Tumor Growth. 
Wang M*, Hossain MS, Tan WL, Brett C, Zhou J, Liu S, and Casey PJ. (2010)
Oncogene. 29:4959-70. (*Corresponding author). PMID: 20622895

A high-performance liquid chromatography method for the quantification of cysmethynil, an inhibitor of isoprenylcysteine carboxylmethyl transferase, in mouse plasma.
Wang M, Khoo YM, Zhou J, Casey PJ, and Lee HS (2009) 
J Chromatogr B Analyt Technol Biomed Life Sci. 2009; 877:553-557. PMID: 19157999

A Small Molecule Inhibitor of Isoprenylcysteine Carboxylmethyltransferase Induces Autophagic Cell Death in PC3 Prostate Cancer Cells.
Wang M, Tan W, Zhou J, Leow J, Go M, Lee HS and Casey PJ (2008) 
J Biol Chem. 283(27):18678-84. PMID: 18434300

Isoprenylcysteine carboxylmethyltransferase as a target for development of novel cancer therapeutics.
Wang M. & Casey, P.J (2006)
Drugs of the Future. 31:437-445.

Klionsky DJ et al (2012) Guidelines for the use and interpretation of assays for monitoring autophagy.Autophagy. 8(4): 445-544. 

Klionsky DJ et al (2016) Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy. 12:1-222.