MERIT Award Recipient: Amato Giaccia, Ph.D.

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Sponsoring NCI Division: Division of Cancer Biology (DCB)
Grant Number: R37 CA088480
Award Approved: June 2010
Institution: Stanford University
Department: Radiation Oncology
The Giaccia Lab
Literature Search in PubMed

Hypoxia and Gene Repression

One of the fundamental differences between normal and tumor tissue is the tumor vasculature (blood vessels). As a solid tumor expands in size, the rate of cancer cell division surpasses the ability of the existing vasculature to supply factors that are necessary for its growth, in particular nutrients and oxygen. A distinct feature of solid tumors is low oxygen tension, or hypoxia. Because the vasculature cannot sustain the growth demands of the cancer cells, solid tumors are invariably less well oxygenated compared to their normal tissue of origin. Therapeutically, hypoxia represents several problems in the treatment of cancer. The effectiveness of radiation therapy is directly related to the amount of oxygen in the tumor. Radiation therapy specifically requires molecular oxygen to form cytotoxic, DNA double-strand breaks that result in chromosome aberrations and cell lethality. Therefore, oxygen is limiting under hypoxic conditions and reduces the efficacy of radiotherapy. In contrast, chemotherapeutic agents that are the most effective against rapidly proliferating tumor cells are limited in their accessibility to tumor cells by the abnormal vasculature of the tumor. Previous studies from my laboratory have indicated that hypoxia induces a unique form of cell death (apoptosis) in tumor cells in cell culture, acts as a selective pressure for the expansion of tumor cells possessing diminished apoptotic potential, and co-localizes with apoptotic regions in tumors.

We found that expression of the p53 tumor suppressor gene is increased under hypoxia, driving tumor cells to kill themselves by apoptosis. Our past studies have shown that hypoxia therefore selects for tumor cells that have lost p53 and possess reduced capacity to die by apoptosis, leading to increased resistance to radiation therapy and chemotherapy, and increased risk of metastasis. However, in tumor cells that do retain p53 function, analysis of the mechanism by which hypoxic cells induce apoptotic cell death suggests that there are essential changes in gene expression, some of which are controlled by p53. We have found that JARID1B is a p53 target gene and functions to regulate expression of other key “down-stream” genes. The discovery that JARID1B is regulated by p53 raises the intriguing possibility that JARID1B represents a unique mechanism that inhibits gene expression, aiding p53 function during DNA damage and hypoxia. The studies outlined in this MERIT award will determine the importance of JARID1B targets under hypoxia and after exposure to ionizing radiation in cell culture and in tumors, characterize the importance of p53 in mediating repression under hypoxia, and determine the contribution of JARID1B to tumor progression using mouse tumor models.