Abstract 5163: JMJD1a: A potential target for prevention and therapy in pancreatic cancer

Abstract

Abstract Purpose: Pancreatic cancer is the fourth leading cause of cancer related death in the United States. Therapeutic options for patients with advanced disease are time limited and non-curative. A growing body of evidence suggests that cancer stem cells (CSCs) within a solid tumors including in pancreatic cancer initiate and sustain tumor growth. Our preliminary data implicates Jumanji demethylases1a (JMJD1a) as a prime regulator of stem cell renewability for cancer progression. Hypoxia most prominently controls malignant properties of cancer cells by stimulating hypoxia inducible factor 1 (HIF1). HIF1 binds to its response elements (HREs) in the JMJD1a promoter and subsequently up-regulates JMJD1a. This could explain why hypoxia exacerbates malignancy. Therefore, we hypothesize that hypoxia induces JMJD1a that regulate self-renewability of CSCs, thereby promoting tumor initiation. Recently, two small molecules analogues of crocetinic acid, a carotenoid molecule isolated from saffron, have revealed to have potent antimitotic effects in pancreatic cancer models. Experimental Procedure: We have studied pancreatic CSCs during hypoxic and normoxic conditions allow to form multicellular spheroids called pancospheres and monitored expression of JMJD1a using western blots and immunohistochemistry on those CSCs. We also used shRNA to silence JMJD1a using lentiviral vectors in different pancreatic cancer cell lines. Results: JMJD1a was significantly overexpressed in human pancreatic cancer patient samples compared to their adjacent normal tissues. JMJD1a is overexpressed in pancreatic cancer cells and it is significantly reduced when it is knocked down through shRNA in those cell lines. The colony formation and migration assays were significantly reduced after knock-down of JMJD1a. Hypoxia stimulated pancospheres formation associated with concomitant overexpression of JMJD1a. Knock-down of JMJD1a using shRNA demonstrated significant reduction of pancospheres forming ability in both normoxic and hypoxic conditions. The demethylation of specific substrate of JMJD1a, H3-K9me2, was significantly increased by knock-down of JMJD1a in pancreatic cancer cells. Hypoxia significantly increases overexpression of cancer stem-cell and angiogenic markers in pancreatic cancer cells in vitro. Knock-down of JMJD1a significantly affected stem-cell specific markers in both hypoxia and normoxia. Treatment with gemcitabine did not affect in JMJD1a expression in those cell lines particularly during hypoxic conditions. Crocetinic acid and its analogues inhibited JMJD1a expression in both in vivo and in vitro pancreatic cancer models. Conclusions: JMJD1a is overexpressed in pancreatic cancer and stimulates the self-renewability of pancospheres. In conclusion, JMJD1a is one of important factor for pancreatic cancer progression and could be a novel preventive and therapeutic target for pancreatic cancer. Citation Format: Kanagaraj Palaniyandi, Santanu Paul, Parthasarathy Rangarajan, Deep Kwatra, Satish Ramalingam, Dharmalingam Subramaniam, Tomoo Iwakuma, Subhash Padhye, Shrikant Anant, Animesh Dhar. JMJD1a: A potential target for prevention and therapy in pancreatic cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5163. doi:10.1158/1538-7445.AM2014-5163