c-MYC Suppresses BIN1 to Release Poly(ADP-Ribose) Polymerase 1: A Mechanism by Which Cancer Cells Acquire Cisplatin Resistance

Sci. Signal., 29 March 2011
Vol. 4, Issue 166, p. ra19
DOI: 10.1126/scisignal.2001556

c-MYC Suppresses BIN1 to Release Poly(ADP-Ribose) Polymerase 1: A Mechanism by Which Cancer Cells Acquire Cisplatin Resistance

  1. Slovénie Pyndiah1,2,*,,
  2. Satoshi Tanida1,2,*,,
  3. Kazi M. Ahmed3,4,*,,
  4. Erica K. Cassimere1,2,3,4,,
  5. Chungyoul Choe1,2, and
  6. Daitoku Sakamuro1,2,3,4,#
  1. 1Molecular Signaling Program, Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
  2. 2Department of Pathology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
  3. 3Cell Growth and Differentiation Program, Purdue Cancer Center–Walther Cancer Institute, Purdue University, West Lafayette, IN 47907, USA.
  4. 4Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA.
  1. #To whom correspondence should be addressed. E-mail: dsakam{at}lsuhsc.edu
  • * These authors contributed equally to this work.

  • Present address: Hôpital St. Louis, Institut de Génétique Moléculaire, Cibles Thérapeutiques, INSERM U940, F-75010 Paris, France.

  • Present address: Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya 467, Japan.

  • Present address: Department of Cancer and DNA Damage Responses, Ernest Orlando Lawrence Berkeley National Laboratory, Berkeley, CA 94710, USA.

  • Present address: Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, TX 77030, USA.

Abstract

Cancer cells acquire resistance to DNA-damaging therapeutic agents, such as cisplatin, but the genetic mechanisms through which this occurs remain unclear. We show that the c-MYC oncoprotein increases cisplatin resistance by decreasing production of the c-MYC inhibitor BIN1 (bridging integrator 1). The sensitivity of cancer cells to cisplatin depended on BIN1 abundance, regardless of the p53 gene status. BIN1 bound to the automodification domain of and suppressed the catalytic activity of poly(ADP-ribose) polymerase 1 (PARP1, EC 2.4.2.30), an enzyme essential for DNA repair, thereby reducing the stability of the genome. The inhibition of PARP1 activity was sufficient for BIN1 to suppress c-MYC–mediated transactivation, the G2-M transition, and cisplatin resistance. Conversely, overexpressed c-MYC repressed BIN1 expression by blocking its activation by the MYC-interacting zinc finger transcription factor 1 (MIZ1) and thereby released PARP1 activity. Thus, a c-MYC–mediated positive feedback loop may contribute to cancer cell resistance to cisplatin.

Citation:

S. Pyndiah, S. Tanida, K. M. Ahmed, E. K. Cassimere, C. Choe, and D. Sakamuro, c-MYC Suppresses BIN1 to Release Poly(ADP-Ribose) Polymerase 1: A Mechanism by Which Cancer Cells Acquire Cisplatin Resistance. Sci. Signal. 4, ra19 (2011).

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