- Karmanos Cancer Institute
- Location: Detroit, MI
- Job Number: 7069829
- Posting Date: Sep 15, 2020
- Application Deadline: Open Until Filled
Job DescriptionAn NIH-sponsored Postdoc or Research Assistant/Associate position is currently available in Dr. Mary Zhang’s lab at Karmanos Cancer Institute in Detroit, Michigan. Strong biochemistry, molecular biology, and mouse model background are preferred but not required. Dr. Zhang Lab’s research interest, current projects, and selected publications are as follows. Interested candidates should send an email to firstname.lastname@example.org.
Dr. Zhang’s lab has a long-standing interest in the enzymes responsible for post-translational modifications with a particular interest in histone deacetylase 6 (HDAC6) and ubiquitin-specific peptidase 10 (USP10). Her lab was the first to show that HDAC6 harbors a novel ubiquitin E3 ligase activity and participates in the DNA damage response and DNA repair. Her lab was among the first to reveal that both HDAC6 and USP10 are associated with cisplatin sensitivity in lung and ovarian cancers. Her lab currently focuses on elucidating the role of HDAC6 and USP10 in lung cancer initiation, progression, the DNA damage response, DNA repair, cell death, chemosensitivity, and immune responses, using biochemical approaches as well as various cell lines, mouse models, and patient samples. The ultimate goal of her lab’s research is to identify novel therapeutic targets and biomarkers to improve cancer treatment and the overall survival of patients.
1) To elucidate the mechanism by which HDAC6 regulates the DNA damage response Based on our previous observations, we hypothesize that HDAC6 governs the turnover of a group of proteins in the DNA damage response network. We will first unveil the structural basis of HDAC6’s ubiquitin E3 ligase activity. We will then identify the novel substrates of HDAC6’s E3 ligase activity by SILAC assays in lung cancer cells. Finally, we will determine the role of HDAC6 in oncogenesis in genetically engineered lung cancer mouse models and evaluate whether the expression of HDAC6 is associated with cisplatin responses in lung cancer patients.
2) To target HDAC6’s E3 ligase activity in lung cancer to sensitize patients to chemotherapy
Because the catalytic center of HDAC6’s E3 ligase activity has yet to be discovered, we cannot directly target HDAC6. We have found that USP10 is a stabilizer of HDAC6 and will use existing USP10 inhibitors to decrease the expression of HDAC6. We will collaborate with a medicinal chemist to improve the potency and specificity of the current USP10 inhibitors and test the new inhibitors in in vitro assays and in in vivo lung cancer cell lines and animal models.
3) To elucidate the role of USP10 in host immune responses
We recently found that USP10 regulates STAT3 (signal transducer and transcription activator-3), a transcription factor, which in turn regulates immune checkpoint molecule PD-L1. Our nanostring assays have further shown that in addition to PD-L1, USP10 governs the mRNA expression of several cytokines, such as TGFBased on the above evidence, we hypothesize that USP10 promotes an immune suppressive tumor microenvironment through regulating cytokines and immune checkpoint molecules and that targeting USP10 would increase anti-tumor immunity. To test this hypothesis, we will explore the associations between tumor growth and the changes in lymphocyte phenotypic/functional markers (LPFM) and cytokine responses, which will be measured via multi-factorial immune profiling and cytokine multiplex assays in USP10 conditional knockout mouse models.
1. Hu C, Zhang M, Moses N, Hu CL, Polin L, Chen W, Jang H, Heyza J, Malysa A, Caruso JA, Xiang S, Patrick S, Stemmer P, Lou Z, Bai W, Wang C, Bepler G, Zhang Xiaohong Mary. The USP10-HDAC6 axis confers cisplatin resistance in non-small cell lung cancer lacking wild-type p53. Cell Death Dis 2020 May 7: 11(5):328. PubMed PMID: 32382008; PubMed Central PMCID: PMC7206099
2. Zhang M, Hu C, Moses N, Haakenson J, Xiang S, Quan D, Fang B, Yang Z, Bai W, Bepler G, Li GM, Zhang, Xiaohong Mary. HDAC6 regulates DNA damage response via deacetylating MLH1. J Biol Chem. 2019 Feb 15. pii: jbc.RA118.006374. doi: 10.1074/jbc.RA118.006374. [Epub ahead of print]
3. Zhang M, Xiang S, Joo HY, Wang L, Williams KA, Liu W, Hu C, Tong D, Haakenson J, Wang C, Zhang S, Pavlovicz RE, Jones A, Schmidt KH, Tang J, Dong H, Shan B, Fang B, Radhakrishnan R, Glazer PM, Matthias P, Koomen J, Seto E, Bepler G, Nicosia SV, Chen J, Li C, Gu L, Li GM, Bai W, Wang H, Zhang Xiaohong. HDAC6 deacetylates and ubiquitinates MSH2 to maintain proper levels of MutSα. Mol Cell. 2014 Jul 3;55(1):31-46. PubMed PMID: 24882211; PubMed Central PMCID: PMC4188514.
4. Zhang Xiaohong, Yuan Z, Zhang Y, Yong S, Salas-Burgos A, Koomen J, Olashaw N, Parsons JT, Yang XJ, Dent SR, Yao TP, Lane WS, Seto E. HDAC6 modulates cell motility by altering the acetylation level of cortactin. Mol Cell. 2007 Jul 20;27(2):197-213. PubMed PMID: 17643370; PubMed Central PMCID: PMC2684874.