Areas of Interest
My research focuses on how protein post-translational modifications, especially acetylation and phosphorylation, alter protein function in cancer cells. Recently we have described a molecular mechanism by which histone deacetylase inhibitors, a new class of therapeutic agents for cancer treatment, induce cell death in neuroblastoma cells.
Neuroblastoma is the most common extracranial solid tumor in children, and is often refractory to conventional therapies. Our results show that the histone deacetylase inhibitors in neuroblastoma cell target Bax, a pro-apoptotic protein. In these cells, Bax associates with Ku70, a protein that typically increases chemotherapy resistance and participates in DNA repair, in an acetylation-sensitive manner. Upon histone deacetylase inhibitor treatment, acetylated Ku70 releases Bax, allowing it to translocate to mitochondria and trigger cytochrome c release, leading to caspase-dependent cell death. The regulation of the association and dissociation of Ku70 and Bax is dependent on the level of the CREB-binding protein, CBP, which possesses acetyl transferase activity.
Our results demonstrate that Ku70, Bax, and CBP contribute to a therapeutic response to histone deacetylase inhibitors against neuroblastoma cells and identify the possibility of using these factors to predict clinical responsiveness to histone deacetylase inhibitor treatment.
Honors & Awards
1998-2000 Leukemia Society Special Fellow
1993-1996 National Research Service Award, National Institutes of Health
Cytosolic Ku70 regulates Bax-mediated cell death.
Hada M, Subramanian C, Andrews PC, Kwok RP.
Tumour Biol. 2016; 37: 13903-14.
Regulation of ku70-bax complex in cells.
Hada M, Kwok RP.
J Cell Death. 2014; 7: 11-3.
CREB-binding protein regulates Ku70 acetylation in response to ionization radiation in neuroblastoma.
Subramanian C, Hada M, Opipari AW Jr, Castle VP, Kwok RP.
Mol Cancer Res. 2013; 11: 173-81.
HDAC6 deacetylates Ku70 and regulates Ku70-Bax binding in neuroblastoma.
Subramanian C, Jarzembowski JA, Opipari AW Jr, Castle VP, Kwok RP.
Neoplasia. 2011; 13: 726-34.
Glucose deprivation activates AMPK and induces cell death through modulation of Akt in ovarian cancer cells.
Priebe A, Tan L, Wahl H, Kueck A, He G, Kwok R, Opipari A, Liu JR.
Gynecol Oncol. 2011; 122: 389-95.
CLU blocks HDACI-mediated killing of neuroblastoma.
Subramanian C, Jarzembowski JA, Halsey SM, Kuick R, Opipari AW Jr, Castle VP, Kwok RP.
Tumour Biol. 2011; 32: 285-94.
Trichostatin A restores Apaf-1 function in chemoresistant ovarian cancer cells.
Tan L, Kwok RP, Shukla A, Kshirsagar M, Zhao L, Opipari AW Jr, Liu JR.
Cancer. 2011; 117: 784-94.
For a list of publications from Michigan Research Experts, click HERE