Mortality in cancer is most often due to the development of distant metastases for which almost no effective systemic treatments exist. The study of genes relevant for the regulation of metastasis in vivo is therefore of great importance. The functions of p63, a p53 family member, are beginning to be understood in contexts in which p53 function has been well established, including apoptosis and tumor suppression (Su et al., Nature 2010) as well as in other roles such as metastasis (Su et al., Nature 2010), skin development, and stem cell maintenance (Su et al., Cell Stem Cell 2009). The complexity of p63 function is due in part to the existence of multiple isoforms that previously could not be studied independently. Full length TA isoforms of p63 contain a transactivation domain, structurally and functionally resembling p53, whereas the ?N isoforms of p63, while also possessing transactivation activity, antagonize the activities of p53 and the TA isoforms of p63 and p73, the other p53 family member. Interestingly, mutant p53, present in a wide variety of human cancers, has been shown to interact with p63 isoforms and inactivate their function. By generating and studying mice with isoform-specific null alleles of p63, the TAp63-/- and ?Np63-/- mice, we have shown that these genes have distinct roles in suppression of tumorigenesis and metastasis. TAp63-/- mice are highly susceptible to spontaneous metastatic tumors, and TAp63 potently suppresses tumor metastasis by direct coordinate transcriptional regulation of Dicer and several miRNAs (Su et al., Nature 2010). In addition, we have extended these findings to multiple human tumor types including squamous cell carcinoma, lung adenocarcinoma, and breast adenocarcinoma, indicating this function of TAp63 is widely important. We have also shown that ?Np63 can suppress invasion and transcriptionally regulates DGCR8, another critically important enzyme necessary for miRNA processing. We hypothesize that TAp63 and ?Np63 regulate distinct miRNAs in different cellular compartments to suppress tumorigenesis and metastasis and to engage the DNA damage response. We will address our hypothesis by proposing the following specific aims:
Specific Aim 1 : To understand the mechanistic regulation of miRNA and LincRNA targets by p63 isoforms in the cell of origin of carcinomas (epidermal cells).
Specific Aim 2 : To understand the mechanistic regulation of miRNAs and LincRNAs by p63 isoforms in stem cells of skin cancer and metastasis.
Specific Aim 3 : To understand the roles of miRNAs and LincRNAs regulated by p63 isoforms in the DNA damage response and p53 compensation.

Public Health Relevance

The study of genes relevant for the regulation of metastasis in vivo is of great importance given the high mortality of metastatic cancer, and p63, a p53 family member, plays critical roles to suppress metastasis through coordinate transcriptional regulation of Dicer and microRNAs (miRNAs). The goals of this grant proposal are to identify the miRNA and long non-coding RNA (LincRNA) targets that are regulated by p63 and its isoforms in the suppression of metastasis and the DNA damage response. We will use p63 isoform specific knock out mouse models of metastatic squamous cell carcinoma generated in my laboratory and human patient samples to address this goal.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA160394-03
Application #
8642610
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Mietz, Judy
Project Start
2012-05-01
Project End
2017-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
3
Fiscal Year
2014
Total Cost
$425,671
Indirect Cost
$116,597
Name
University of Texas MD Anderson Cancer Center
Department
Biochemistry
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Abbas, Hussein A; Bui, Ngoc Hoang Bao; Rajapakshe, Kimal et al. (2018) Distinct TP63 Isoform-Driven Transcriptional Signatures Predict Tumor Progression and Clinical Outcomes. Cancer Res 78:451-462
Su, X; Napoli, M; Abbas, H A et al. (2017) TAp63 suppresses mammary tumorigenesis through regulation of the Hippo pathway. Oncogene 36:2377-2393
Napoli, Marco; Venkatanarayan, Avinashnarayan; Raulji, Payal et al. (2016) ?Np63/DGCR8-Dependent MicroRNAs Mediate Therapeutic Efficacy of HDAC Inhibitors in Cancer. Cancer Cell 29:874-888
Venkatanarayan, Avinashnarayan; Raulji, Payal; Norton, William et al. (2016) Novel therapeutic interventions for p53-altered tumors through manipulation of its family members, p63 and p73. Cell Cycle 15:164-71
Wang, Yang; Wang, Xinwei; Flores, Elsa R et al. (2016) Dysfunctional telomeres induce p53-dependent and independent apoptosis to compromise cellular proliferation and inhibit tumor formation. Aging Cell 15:646-60
Venkatanarayan, Avinashnarayan; Raulji, Payal; Norton, William et al. (2015) IAPP-driven metabolic reprogramming induces regression of p53-deficient tumours in vivo. Nature 517:626-30
Chakravarti, Deepavali; Su, Xiaohua; Cho, Min Soon et al. (2014) Induced multipotency in adult keratinocytes through down-regulation of ?Np63 or DGCR8. Proc Natl Acad Sci U S A 111:E572-81
Tan, E H; Morton, J P; Timpson, P et al. (2014) Functions of TAp63 and p53 in restraining the development of metastatic cancer. Oncogene 33:3325-33
Vin, Harina; Ojeda, Sandra S; Ching, Grace et al. (2013) BRAF inhibitors suppress apoptosis through off-target inhibition of JNK signaling. Elife 2:e00969
Napoli, Marco; Flores, Elsa R (2013) The family that eats together stays together: new p53 family transcriptional targets in autophagy. Genes Dev 27:971-4

Showing the most recent 10 out of 19 publications