Research Article: Multiple roles of RARRES1 in prostate cancer: Autophagy induction and angiogenesis inhibition

Date Published: July 5, 2017

Publisher: Public Library of Science

Author(s): Arpita Roy, Malathi Ramalinga, Okjin J. Kim, Juliet Chijioke, Solomon Lynch, Stephen Byers, Deepak Kumar, Gagan Deep.


Prostate cancer (PCa) poses a major health concern in men worldwide. Retinoic Acid Receptor Responder (RARRES1)/ Tazarotene-induced gene-1 (TIG-1) is a putative tumor suppressor gene that exerts its tumor suppressor function via unknown mechanisms. Epigenetic silencing of RARRES1 leads to its loss in several types of cancer, including PCa. Determining the molecular mechanisms that mediate the tumor suppressor role of RARRES1 in PCa is the focus of our study.

Our data indicates that RARRES1 over expression in PCa cell lines represses mitogen-activated protein kinase (MAPK) activation. RARRES1 expression induces the levels of autophagy-related genes, beclin, ATG3 and increases LC3B-II conversion. A significant induction of SIRT1 along with mTOR inhibition is noted on RARRES1 expression. Furthermore, RARRES1 over expression elevates the levels of the antioxidant enzyme, catalase. Our results also indicate that RARRES1 expression inhibits angiogenesis in endothelial cells.

In summary, the data presented here indicate that forced expression of RARRES1 in PCa cells (a) induces ER stress and autophagic response; (b) increases SIRT1 levels; and (c) higher levels of anti-oxidant enzymes. Our study also implicates the role of RARRES1 as a novel anti-angiogenic molecule. Overall this study reports the molecular players that RARRES1 modulates to serve as a tumor suppressor molecule. Future studies will help determine the in vivo mechanisms by which RARRES1 may serve as a target for therapeutic intervention both in cancer and in angiogenesis-related disorders.

Partial Text

Prostate cancer (PCa) is the most common cancer and a leading cause of cancer death among men in the United States. According to the American Cancer Society, 161,360 new cases and an estimated 26,730 deaths from PCa has been projected in 2017 alone[1]. Retinoic Acid Receptor Responder (RARRES1)/ Tazarotene-induced gene-1 (TIG-1) is a novel retinoid inducible gene first identified in skin raft cultures[2]. Frequent epigenetic inactivation due to aberrant DNA hypermethylation of the RARRES1 promoter results in transcriptional silencing of RARRES1 expression in esophageal, gastric, endometrial and PCa [3–7]. Cellular mechanisms via which RARRES1 exerts its tumor suppressor function have not been elucidated. The present study aims to understand the molecular mechanisms that underlie the functions of RARRES1.

Prostate cancer (PCa) is the most common malignancy in men and is the second leading cause of cancer deaths worldwide. Advances in the study of prostate carcinogenesis suggest a complex and multi-factorial role of epigenetic aberrations in the progression of the disease. The tumor suppressor gene, RARRES1, was reported to be hyper-methylated at its promoter region in several forms of cancer including PCa leading to suppression of RARRES1 [27]. We sought to determine the mechanism by which RARRES1 may function as a tumor suppressor in PCa.




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