KANK1 inhibits cell growth by inducing apoptosis through regulating CXXC5 in human malignant peripheral nerve sheath tumors

Abstract

Malignant peripheral nerve sheath tumors (MPNSTs) are a type of rare sarcomas with a poor prognosis due to its highly invasive nature and limited treatment options. Currently there is no targeted-cancer therapy for this type of malignancy. Thus, it is important to identify more cancer driver genes that may serve as targets of cancer therapy. Through comparative oncogenomics, we have found that KANK1 was a candidate tumor suppressor gene (TSG) for human MPNSTs. Although KANK1 is known as a cytoskeleton regulator, its tumorigenic function in MPNSTs remains largely unknown. In this study, we report that restoration of KANK1 in human MPNST cells inhibits cell growth both in human cell culture and xenograft mice by increasing apoptosis. Consistently, knockdown of KANK1 in neurofibroma cells promoted cell growth. Using RNA-seq analysis, we identified CXXC5 and other apoptosis-related genes, and demonstrated that CXXC5 is regulated by KANK1. Knockdown of CXXC5 was found to diminish KANK1-induced apoptosis in MPNST cells. Thus, KANK1 inhibits MPNST cell growth though CXXC5 mediated apoptosis. Our results suggest that KANK1 may function as a tumor suppressor in human MPNSTs, and thus it may be useful for targeted therapy.

CXXC5: A novel regulator and coordinator of TGF‐β, BMP and Wnt signaling

“…We found that CXXC5 is also downregulated in the majority of HCC tissue samples, leading to breakdown of CXXC5‐mediated positive feedback regulation of TGF‐β signaling and attenuation of its anti‐proliferative effects . In addition, CXXC5 is involved in KANK1‐induced cell growth inhibition and apoptosis in MPNSTs . However, it has also been shown that CXXC5 is overexpressed in ER+ breast cancer and associated with poor prognosis in patients .…”

“…KANK1 is a potential tumour suppressor gene and is downregulated in more than half of human malignant peripheral nerve sheath tumours (MPNSTs) . Overexpression of KANK1 could induce CXXC5 expression to promote cell apoptosis in MPNSTs . The retinoic acid receptor (RARα) acts as a transcription factor when bound to all‐trans retinoic acid, facilitating terminal maturation of leukaemic blasts .…”

“…78 Overexpression of KANK1 could induce CXXC5 expression to promote cell apoptosis in MPNSTs. 79 The retinoic acid receptor (RARα) acts as a transcription factor when bound to all-trans retinoic acid, facilitating terminal maturation of leukaemic blasts. 80 The CXXC5 promoter contains a reti- Nd., not determined; ATM, ataxia telangiectasia mutated; VDR, vitamin D receptor; TGF-β, transforming growth factor beta.…”

“…10 In addition, CXXC5 is involved in KANK1-induced cell growth inhibition and apoptosis in MPNSTs. 79 However, it has also been shown that CXXC5 is overexpressed in ER+ breast cancer and associated with poor prognosis in patients. 84 This is in agreement with the observation that CXXC5 is upregulated by E2-ERα.…”

miR‐32 promotes esophageal squamous cell carcinoma metastasis by targeting CXXC5

“…34,35 More importantly, CXXC5 acted as a potential tumor suppressor, and it is the target gene of miR-32. 34,35 More importantly, CXXC5 acted as a potential tumor suppressor, and it is the target gene of miR-32.…”