A Truncated Form of IKKα Is Responsible for Specific Nuclear IKK Activity in Colorectal Cancer

Abstract

Nuclear IKKα regulates gene transcription by phosphorylating specific substrates and has been linked to cancer progression and metastasis. However, the mechanistic connection between tumorigenesis and IKKα activity remains poorly understood. We have now analyzed 288 human colorectal cancer samples and found a significant association between the presence of nuclear IKK and malignancy. Importantly, the nucleus of tumor cells contains an active IKKα isoform with a predicted molecular weight of 45 kDa (p45-IKKα) that includes the kinase domain but lacks several regulatory regions. Active nuclear p45-IKKα forms a complex with nonactive IKKα and NEMO that mediates phosphorylation of SMRT and histone H3. Proteolytic cleavage of FL-IKKα into p45-IKKα is required for preventing the apoptosis of CRC cells in vitro and sustaining tumor growth in vivo. Our findings identify a potentially druggable target for treating patients with advance refractory CRC.

Active nuclear IKK correlates with metastatic risk in cutaneous squamous cell carcinoma

“…However, since IKK activity is also essential for multiple physiological functions in the organism [18,24,26,31,33,34,50], and most IKK inhibitors do not show any isoform specificity, novel compounds (working at lower IC50 range if possible) should be specifically designed for therapeutic purpose. In Arch Dermatol Res this sense, we recently identified a novel IKKa isoform, with a molecular weight of 45 kDa, that is essential for tumour cell growth and is associated with increased tumour grade in colorectal cancer samples [27], but is also the main contributor to nuclear IKK activity in A431 cells. Although we have not determined yet whether p45-IKKa is also responsible for nuclear IKK activity in primary human cSCC tumours, we propose that molecules specifically targeting IKKa and/or its processing into p45-IKKa could represent a future therapy for treating metastatic cSCC.…”

“…The IKK complex is composed of IKKa, IKKb and NEMO, being the IKKb subunit essential for NF-jB activation and for the regulation of the immune system and organism fitness [8,12,22]. IKKa is not required for these functions, but it is necessary to signal through the alternative NF-jB pathway (that signals through the p52/RelB heterodimer), and to phosphorylate specific nuclear substrates such as histone H3, SMRT and N-CoR thus facilitating NF-jBdependent and NF-jB-independent transcription [6,7,16,17,27,48]. In a mouse model for prostate cancer, nuclear active IKKa represses transcription of the anti-metastatic gene Maspin by direct binding to its promoter region.…”

A network-based analysis of colon cancer splicing changes reveals a tumorigenesis-favoring regulatory pathway emanating from ELK1

“…Other events are not specifically known to be involved in cancer development but are located within genes that are: TPM1, DNMT3B, NCOR2 (also known as SMRT), and SLK (Jin et al 2009;Roovers et al 2009;Choi et al 2012;Margalef et al 2012). As the total number of nucleotides in some of these alternative segments is not a multiple of three, their respective addition or deletion from the mRNA is likely to cause a premature stop codon, which could lead to the formation of a truncated protein or to mRNA degradation via nonsensemediated mRNA decay (NMD).…”

High IKKα expression is associated with reduced time to recurrence and cancer specific survival in oestrogen receptor (ER)‐positive breast cancer

“…IKKα independent of the non-canonical NF-B pathway 10,[34][35][36] and this been suggested to be via a truncate form of IKKα (p45 IKKα) that is constitutively active and specifically resides in the nucleus 10 . In the discovery cohort, when Luminal A tumours were considered only nuclear IKKα remained independently associated with cancer-specific survival.…”

“…These complexes translocate to the nucleus and regulate transcription of a variety of genes important in apoptosis, proliferation, invasion and adaptive immunity [7][8][9] . Therefore it is not surprising that studies have demonstrated dysregulation of the non-canonical NF-B pathway in many solid tumours 10,11 . More recently the non-canonical NF-κB pathway has been implicated in the development and progression of breast cancer 12 .…”